bims-imseme 2026-10-04 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–10–04
forty-one papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Coupling and uncoupling cell cycle and metabolism in CD8+ T cells.
In vivo CRISPR Screening Reveals LBR as a Regulator of CD8+ T Cell Fate Decision.
Context-dependent regulation of cytotoxic T lymphocytes by nuclear receptors.
Extracting interpretable single-cell metabolic states with graph-guided representation learning.
TFAM Dependent Mitochondrial Fitness Limits CD8⁺ T Cell Immunopathology and Sustains Protective Immunity during Viral Pneumonia.
SPRED2 Negatively Regulates CD8+ T Cell-Mediated Antitumor Immunity in Breast Cancer.
Systemic iron sequestration restricts the intratumoral CD8+ T cell landscape in pancreas cancer.
Unique CD8 + T Cell Populations Expand during ART and Predict Delayed HIV-1 Rebound.
Ras protein activator-like 3 is a key Ras GTPase-activating protein that protects the survival and anti-tumor activity of CD8+ T cells.
In vivo-edited CCR7+IL-7+ DCs reverse T cell exhaustion by promoting T memory stem cell differentiation.
Aging-associated SATB1 deficiency remodels 3D genome architecture and transcriptional programs in naive CD4+ T cells.
High ZFP36 Family Expression in Exhausted T Cells Is Associated With Impaired Antitumor Effector Function.
Correction: Stem-like CD4 T cells in tumors: an emerging framework for antitumor immunity.
Investigating CD8 T Cell Exhaustion in Chronic LCMV Infection by Flow Cytometry.
CAR signaling instructs divergent metabolic reprogramming and functional fates in αβ and γδ T cells.
Peripheral CXCR3 blockade mitigates T cell infiltration and neurodegeneration in a mouse model of tauopathy.
IL-2/CD25 acts within the tumor microenvironment to reprogram tumor-specific cytotoxic CD8+ T cells while restraining regulatory T-cell accumulation.
A Multi-Targeting Chimeric Antigen Receptor-T Cell Platform to Overcome Antigen Heterogeneity in the Treatment of Non-Small Cell Lung Cancer.
Type 1 diabetes SIRPG risk variants increase SIRPγ expression and CD47 loss enhances CD8+ T cell cytotoxicity.
Multiparametric Flow Cytometry Analysis of Naïve, Memory, and Effector T-Cells.
NETs drive CD4⁺ T cell dysfunction in sepsis via mitochondrial ROS and impaired calcium signalling.
Metabolic dysfunction and GZMK+ CD8+ T-cell remodeling in hepatocellular carcinoma: an evidence-stratified, hypothesis-generating review.
Macrophage Trogocytosis of Tumor Cells Drives the Immunosuppression of Tumor Microenvironment.
Age-associated Autoimmunity Driven by T cell Immunosenescence.
Spatially confined IL-12 programs CAR-NK through mTORC1 to coordinate antitumor immune networks.
Thy1 retroviral reporters: a versatile platform for congenic background-independent adoptive transfer and CD8+ T cell differentiation studies.
Understanding the Mechanistic Connection between Dysbiosis and Polyamine Regulation in Oral and Intestinal Inflammation- Role of Tregs and Th17 Cells.
Potentiating immunotherapy in "immune-cold" solid tumors through orchestrating T cell immunity via tumor-specific genetic engineering.
Chemotherapy enhances cancer vaccine efficacy and expands stem-like TCF1+CD8+ T cells.
OX40 ligand-engineered dendritic cell nanovesicles potentiate antitumor immunity through dual-mode T cell activation.
Metabolic licensing and restriction of innate immunity in the tumor microenvironment.
α-aminobutyric acid promotes tumor progression by polarizing macrophages through the ASNS-mTORC2 axis.
A systematic transcriptomic atlas and predictive framework for metabolite-driven T cell state transitions.
TIGIT regulates CD8+T cell exhaustion via the PI3K/AKT-FOXO1-TOX axis in extrahepatic cholangiocarcinoma.
[Research on the Immunotherapy of T Cell Exhaustion in Multiple Myeloma --Review].
INHBB Promotes Colorectal Cancer Progression by Inducing CD8+ T Cell Exhaustion via the ACVR2B-SMAD Signaling Axis.
Immune remodeling of tumor-draining lymph nodes: mechanistic determinants of checkpoint blockade responsiveness.
Immune responses following myocardial infarction in aged mice.
Galectin-3 restrains T cell-driven inflammation in the testis and epididymis.
Refinement of the Pathogenic T Cell Receptor Motif Suggests Type 17 CD8+ T Cells Initiate HLA-B*27-associated Autoimmunity.
A positively selected microRNA controls a reversible aging program in striated muscle.

Trends Immunol. 2026 Sep 29. pii: S1471-4906(26)00256-5. [Epub ahead of print]

Coupling and uncoupling cell cycle and metabolism in CD8+ T cells.

Floortje J van Haften, Hanna S Hepp, Melissa Biemond, Ramon Arens.

  CD8+ T cells eliminate infected and malignant cells through coordinated proliferation and effector differentiation, processes supported by metabolic reprogramming that together form an interconnected, cross-regulated network. Emerging evidence indicates, however, that cell cycle progression and effector programming can be transiently uncoupled, with implications for T cell function and fate. Short-term modulation of cell cycle dynamics creates a window for metabolic rewiring, reshaping nutrient utilization, cytokine responsiveness, and bioenergetic capacity. This uncoupling can enhance T cell expansion, effector function, and antitumor activity. Collectively, these findings indicate that the cell cycle functions as an instructive checkpoint integrating metabolic and differentiation programs, not merely supporting proliferation. Understanding this interplay provides a conceptual framework to optimize T cell-based immunotherapies and rationally design chemoimmunotherapy combinations.

Keywords:  CD8(+) T cells; T cell differentiation; adoptive cell transfer; cell cycle progression; immunotherapy; metabolic reprogramming

DOI:  https://doi.org/10.1016/j.it.2026.09.001
FASEB J. 2026 Oct 15. 40(19): e72318

In vivo CRISPR Screening Reveals LBR as a Regulator of CD8+ T Cell Fate Decision.

Qiying Zhang, Shuya Chang, Shengli Zhao, Weixin Zhang, Rong Wang, Mingyang Zhong, Guanfeng Liu, Xiaojing Li, Ao Guo.

  CD8+ T cells play an important role in anti-infection and anti-tumor immunity. Metabolic reprogramming has emerged as a critical regulator of T cell function, yet the roles of specific cholesterol-associated proteins during T cell fate trajectories remain unclear. Here, using an in vivo CRISPR screen in CD8+ T cells during infection with a customized sgRNA library targeting key cholesterol metabolism-associated proteins, we successfully identified several candidate targets, including the LBR (Lamin B Receptor). Lbr knockout significantly reduced the proportion and absolute number of short-lived effector cells (SLECs), severely impairing effector responses, while concomitantly increasing the memory precursor population upon LCMV infection. Furthermore, transcriptomic analysis revealed that Lbr depletion markedly altered signaling pathways governing effector T cell differentiation. These findings reveal the role of LBR in modulating effector and memory T cell differentiation, suggesting it as a potential target for metabolic reprogramming to enhance T cell-based immunotherapies.

Keywords:  CD8+ T cells; LBR; T cell fate decisions; cholesterol metabolism; in vivo CRISPR screen

DOI:  https://doi.org/10.1096/fj.202602909R
J Immunol. 2026 Oct 01. pii: vkag261. [Epub ahead of print]215(10):

Context-dependent regulation of cytotoxic T lymphocytes by nuclear receptors.

Chang H Kim.

  Cytotoxic CD8⁺ T lymphocytes eliminate pathogen-infected and malignant cells through migration to affected tissues, cytokine production, and cytotoxic activity. A mounting body of evidence indicates that CD8 T cell differentiation into functionally different subsets, such as effector, memory, tissue-resident memory, and exhausted T cells, is controlled by a group of nuclear receptors (NRs). NRs sense signals from various physiological and environmental cues, such as nutritional, endocrine, stress/circadian, and metabolic signals, and translate them into gene-regulatory decisions. NRs act through direct and indirect DNA binding, corepressor-coactivator exchange, and transrepression of effector-associated transcription factors, thereby reshaping chromatin accessibility and metabolic programs during CD8 T cell differentiation. This review highlights major CD8 T cell-regulating pathways involving vitamin A-sensing RAR-α, sterol-responsive LXR-β and ROR-α, orphan NR4A proteins; vitamin D receptor (VDR), glucocorticoid receptor (GR), and androgen receptor (AR). Understanding the shared and separable functions of NRs and their ligands provides insights into therapeutic strategies, such as pharmacologic modulation, checkpoint blockade, and chimeric antigen receptor T cell therapies, to promote durable antitumor and antiviral CD8 T cell activities.

Keywords:  CD8⁺ T cells; differentiation; effector; exhausted T cells; nuclear receptors

DOI:  https://doi.org/10.1093/jimmun/vkag261
bioRxiv. 2026 Sep 24. pii: 2026.09.17.751504. [Epub ahead of print]

Extracting interpretable single-cell metabolic states with graph-guided representation learning.

Daniel P Lewinsohn, Nicolas Dias, Adelina Chau, Yuko Koike, Zachary D Smith, Nilah M Ioannidis, Allon Wagner.

Metabolism shapes cellular function and state, yet measuring single-cell metabolic states at scale remains a challenge. We present Metabolic Representation Net (MeRN), a graph-guided variational autoencoder that leverages prior metabolic knowledge as a topology graph to learn latent representations of metabolic state and reaction activity from single-cell transcriptomes. MeRN's scalable estimation of reaction activity enables the definition of data-driven pathways (DDPs): context-specific metabolic modules supported by transcriptomic evidence and agnostic of standard pathway definitions. Using DDPs, we introduce the weakest link analysis to identify metabolic network rewiring. MeRN recovers metabolic zonation in the mouse intestine, links a folate deficiency-induced break in de novo purine synthesis to embryonic neural tube defects, shows cytokines with similar non-metabolic effects can elicit divergent T cell metabolism, and identifies metabolic drivers of T cell exhaustion and therapy response in human cancers. Our results establish MeRN as a unified method for metabolic analysis of single-cell transcriptomes.
Research highlights: MeRN leverages the metabolic topology to comprehensively predict reaction- and pathway-level metabolic activitiesMeRN enables data-driven pathways (DDPs) that capture empirically supported cell-type-specific metabolic modules, agnostic of standard pathway definitions MeRN-based DDPs identify metabolic network rewiring of de novo purine synthesis due to folate deficiency during embryonic neural tube development MeRN identifies human pan-cancer metabolic drivers of T cell exhaustion and Treg-specific metabolic adaptations.

DOI: https://doi.org/10.64898/2026.09.17.751504
bioRxiv. 2026 Sep 27. pii: 2026.09.24.754254. [Epub ahead of print]

TFAM Dependent Mitochondrial Fitness Limits CD8⁺ T Cell Immunopathology and Sustains Protective Immunity during Viral Pneumonia.

Zahrasadat Navaeiseddighi, Kai Guo, Syed Shafat Hasan, Zhihan Wang, Rutuparnna Mishra, Taylor Schmit, Jamanah Ahsan, Emily J Moser, Junguk Hur, Jacob S Yount, Ramkumar Mathur, Liang Zhou, Nadeem Khan.

During respiratory virus infection, CD8⁺ T cells kill infected cells and establish antigen-specific memory, but mechanisms regulating these functions remain incompletely understood. Here, we identify mitochondrial transcription factor A (TFAM)-dependent mitochondrial fitness as a regulator of CD8⁺ T cell function during influenza infection. Human CD8⁺ T cells exhibited an age-associated decline in TFAM expression and mitochondrial function. To model this physiologically relevant decline and determine its consequences for antiviral immunity, we generated CD8⁺ T cell-specific TFAM-haploinsufficient mice. TFAM insufficiency disrupted mitochondrial integrity and bioenergetics and increased mitochondrial DNA and oxidative stress. During influenza infection, TFAM-insufficient CD8⁺ T cells exhibited increased cytotoxic and inflammatory activity associated with lung immunopathology without improved viral control. This early phenotype was followed by loss of effector function, diminished antigen-specific responses, reduced protection following adoptive transfer, and impaired heterosubtypic recall immunity. Thus, TFAM-dependent mitochondrial fitness is a cell-intrinsic regulator that limits immunopathology while sustaining recall immunity.

DOI: https://doi.org/10.64898/2026.09.24.754254
Adv Sci (Weinh). 2026 Sep 27. e77909

SPRED2 Negatively Regulates CD8+ T Cell-Mediated Antitumor Immunity in Breast Cancer.

Miao Tian, Teizo Yoshimura, Kun Zhao, Chunning Li, Tong Gao, Ziyi Wang, Masayoshi Fujisawa, Toshiaki Ohara, Akihiro Matsukawa.

  Activation of the RAS/RAF/ERK pathway is crucial for adaptive immunity. Here, we provide evidence that Sprouty-related EVH1 domain containing 2 (SPRED2), an endogenous inhibitor of this pathway, negatively regulates CD8+ T cell-mediated antitumor immunity in breast cancer. In EO771 and 4T1 mouse models, Spred2-/- mice exhibit reduced tumor growth, with lower endpoint lung metastatic burden in the 4T1 model, accompanied by increased T-cell infiltration and activation. Spred2-/- T cells show enhanced cytokine expression, proliferation, survival, in vitro cytotoxicity, and memory-like phenotypes, particularly among CD8+ T cells. Adoptive transfer of Spred2-/- CD8+ T cells into tumor-bearing wild-type hosts similarly reduces endpoint lung metastatic burden. MEK inhibition with U0126 attenuates increased interferon-gamma and granzyme B expression in Spred2-/- CD8+ T cells. Transcriptomic analyses reveal an inverse correlation between SPRED2 expression and antitumor CD8+ T cell states in both humans and mice. In tumor-infiltrating T cells from patients with breast cancer, SPRED2low T cells show enriched effector and cytotoxicity programs and are associated with "immune-hot" tumors, whereas survival associations vary with CD8+ T cell context. Collectively, these findings suggest that SPRED2 functions as a cell-intrinsic negative regulator of CD8+ T-cell activation and highlight its potential as a therapeutic target to enhance T cell-based cancer immunotherapy.

Keywords:  CD8+ T cells; MAPK/ERK; breast cancer; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1002/advs.77909
bioRxiv. 2026 Sep 25. pii: 2026.09.21.753167. [Epub ahead of print]

Systemic iron sequestration restricts the intratumoral CD8+ T cell landscape in pancreas cancer.

Joshua Schoenfeld, Jahi Noel, Christopher McGinnis, Chenlian Fu, Brinda Alagesan, Eduardo Hernandez, Justin Jee, Nikolaus Schultz, Quaid Morris, Scott Lowe, Suzanne Cloonan, John Connolly, Ronan Chaligne, David Kelsen, Kenneth Yu, William Zhang, Eileen OReilly, Ansuman Satpathy, Tomas Ganz, Santosha Vardhana.

Systemic iron sequestration occurs frequently in cancer due to inflammation-driven expression of the iron-regulatory hormone hepcidin. The impact of systemic iron availability on tumoral immunity is unclear. Here, we show that elevated serum hepcidin is associated with reduced survival and decreased intratumoral CD8+ T cells in patients with pancreas cancer. While hepcidin is not induced in murine tumor models, administration of a hepcidin mimetic phenocopies the T-cell-depleted tumor microenvironment seen in patients. Mechanistically, chronic antigen-driven mitochondrial dysfunction disrupts iron metabolism and selectively depletes high avidity CD8+ T cells during iron restriction. These findings establish a direct link between hepcidin-mediated iron sequestration and tumoral immunity and nominate systemic iron dysregulation as a therapeutic target to enhance anti-tumoral CD8+ T cell responses.

DOI: https://doi.org/10.64898/2026.09.21.753167
bioRxiv. 2026 Aug 15. pii: 2026.08.11.743993. [Epub ahead of print]

Unique CD8 + T Cell Populations Expand during ART and Predict Delayed HIV-1 Rebound.

RV254 study team

Antiretroviral therapy (ART) suppresses HIV-1 replication but does not eliminate the latent reservoir, resulting in viral rebound with variable kinetics after treatment interruption. How the immune cell states established during ART influences timing of rebound is not fully understood. In this study, we analyzed 111 participants across multiple cohorts, with 188 single-cell multiomic samples generated and integrated for joint analysis. Longitudinal profiling of peripheral blood mononuclear cells from individuals with acute HIV-1 infection on ART, spanning early infection through sustained therapy and pre-analytical treatment interruption, revealed that time to viral rebound was driven not by global changes in immune composition but by dynamic transcriptional programs within CD8 + T cells. During ART, there was a dramatic expansion of a unique cluster of poised naïve CD8 + T cells, with a distinct immune state positioned upstream of stem-like memory CD8 + T cells along a cell differentiation continuum. The differential abundance of this poised naïve CD8 + T cell population was enriched in participants with delayed rebound and showed strong predictive power for discriminating time to rebound. Mechanistically, the poised naïve CD8 + T cells exhibited features of a precursor phenotype of stem-like memory CD8 + T cells, and showed activation of the TNFα-NF-κB signaling pathway and increased chromatin accessibility at AP-1 motifs. Notably, both poised naïve CD8 + T cells and stem-like memory CD8 + T cells were consistently enhanced during ART in both acute and chronic infection. In participants who received investigational therapeutic vaccination, the dominant predictive signal shifted downstream along the differentiation trajectory, with stem-like memory CD8 + T cells emerging as the primary determinant of delayed rebound. Together, these findings identify a dynamic CD8 + T cell state continuum as a central determinant of HIV-1 rebound, even in the absence of antigen-specificity, where ART establishes a predictive poised naïve state that can be further leveraged by vaccination to enhance protective stem-like memory responses.

DOI: https://doi.org/10.64898/2026.08.11.743993
Front Immunol. 2026 ;17 1893111

Ras protein activator-like 3 is a key Ras GTPase-activating protein that protects the survival and anti-tumor activity of CD8+ T cells.

Zhenzi Peng, Xinyi Zhou, Alato Okuno, Derick Okwan-Duodu, Suguru Saito.

  Ras signaling plays an essential role in immune cell function; however, its activity must be precisely controlled to prevent excessive activation and associated cellular dysfunction. In this study, we identify the leukocyte-specific Ras GTPase-activating protein (RasGAP) RASAL3 as an important regulator of CD8+ T cell homeostasis and anti-tumor immunity. Following T cell receptor (TCR) stimulation, RASAL3-deficient CD8+ T cells display sustained Ras activation, resulting in increased activation-induced cell death (AICD). The surviving RASAL3-deficient CD8+ T cells exhibit impaired effector functions, including reduced cytokine production and decreased tumor-killing activity. Using an in vivo B16-F10 melanoma model, we found that CD8+ T cell-specific RASAL3-deficient mice (R3fl/flCd8-Cre) develop significantly faster tumor growth compared with control mice. Although Programmed death protein 1 (PD-1) blockade partially restores anti-tumor responses in these mice, the therapeutic effect remains markedly weaker than that observed in control animals. In human melanoma samples, RASAL3 expression is reduced in tumor-infiltrating CD8+ T cells. Furthermore, patients with metastatic melanoma show lower RASAL3 expression in primary tumors compared with patients without metastasis, and higher RASAL3 expression in CD8+ T cells within primary lesions is associated with improved overall survival. Together, these findings reveal that RASAL3 is required for the maintenance of CD8+ T cell survival and effector activity. Reduced RASAL3 expression may represent a mechanism by which tumors evade immune surveillance, and RASAL3 expression in CD8+ T cells may serve as a potential biomarker for predicting clinical outcomes in melanoma.

Keywords:  CD8+ T cells; RASAL3; RasGAP; anti-tumor immunity; melanoma

DOI:  https://doi.org/10.3389/fimmu.2026.1893111
Cell Rep Med. 2026 Sep 30. pii: S2666-3791(26)00503-3. [Epub ahead of print] 103086

In vivo-edited CCR7+IL-7+ DCs reverse T cell exhaustion by promoting T memory stem cell differentiation.

Shunli Fu, Qingping Ma, Shuying Gao, Zhenxing Xia, Weiwei Mu, Shuang Liang, Shijun Yuan, Jinhu Liu, Yiming Xia, Xinrui Liu, Leiqiang Han, Yongjun Liu, Na Zhang.

  T cell exhaustion presents a challenge for antitumor immunotherapy. T memory stem cells (Tscms), whose ability to self-renew can continuously generate effector T cells, offering a way to reverse T cell exhaustion. Here, we propose a Tscm regulation strategy involving the construction of dendritic cell (DC)-targeting CCR7/IL-7 mRNA liposomes to edit CCR7+IL-7+ DCs in vivo, thus directly promoting Tscm differentiation within tumor-draining lymph nodes (TDLNs). The antigen-presenting CCR7+IL-7+ DCs migrate to the T-zone within TDLNs via CCR7-mediated signaling and secrete IL-7 to induce naive T cells to differentiate into Tscms. The antigens activate Tscms, promoting continuous Tscm self-renewal and effector T cell generation. The powerful antitumor effects have been observed in B16F10 and 4T1 tumor-bearing mice, and 80% of the mice exhibited suppressed distant tumor formation in the B16F10 prevention model. Overall, this research highlights the importance of Tscm abundance for antitumor immunotherapy and provides high clinical value for developing cancer vaccines.

Keywords:  T cell exhaustion; T memory stem cell; cancer vaccine; dendritic cell; self-renewal; tumor-draining lymph node

DOI:  https://doi.org/10.1016/j.xcrm.2026.103086
Sci Adv. 2026 Oct 02. 12(40): eaeg1622

Aging-associated SATB1 deficiency remodels 3D genome architecture and transcriptional programs in naive CD4+ T cells.

Bao Wang, Luzhang Ji, Qian Bian.

Precise three-dimensional (3D) genome organization is crucial for regulating gene expression during development, yet its role in age-related transcriptional changes and physiological decline remains elusive. Here, we show that aging reshapes chromatin architecture and gene regulation in murine naive CD4+ T cells, a quiescent T cell population essential for adaptive immunity. Aged naive CD4+ T cells exhibit intrinsic transcriptional reprogramming marked by increased expression of inflammatory and T cell activation-related genes, rendering them more prone to activation. Intriguingly, these changes are accompanied by pronounced alterations in 3D genome organization, including widespread weakening of topologically associating domain (TAD) boundaries and extensive enhancer-promoter rewiring. Mechanistically, we demonstrate that these age-associated structural changes can be partly attributed to the diminished expression of chromatin organizer SATB1. SATB1 colocalizes with CCCTC-binding factor (CTCF) in young naive T cells to spatially constrain CTCF-binding sites. Its decline with age extends the range of CTCF-mediated interactions without altering CTCF occupancy, leading to remodeling of chromatin architecture and up-regulation of proinflammatory and proactivation genes. Conditional SATB1 deletion in naive T cells recapitulates the 3D genome and transcriptional changes observed in aging. Our findings reveal a critical role for SATB1 in maintaining 3D genome integrity in naive T cells and suggest that the dysregulation of genome architecture contributes to immune and organismal aging.

DOI: https://doi.org/10.1126/sciadv.aeg1622
Cancer Sci. 2026 Sep 29.

High ZFP36 Family Expression in Exhausted T Cells Is Associated With Impaired Antitumor Effector Function.

Li Zhu, Youki Ueda, Yu Inutsuka, Toshifumi Ninomiya, Yuka Saeki, Takashi Inozume, Hiroko Watanabe, Takamasa Ishino, Hiroyoshi Y Tanaka, Kazuo Yamashita, Masakiyo Sakaguchi, Joji Nagasaki, Yosuke Togashi.

  Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by reinvigorating antitumor immunity; however, a substantial proportion of patients show primary resistance or later relapse. To investigate T cell states associated with reduced ICI efficacy, we performed single-cell RNA sequencing (scRNA-seq) on tumor-infiltrating lymphocytes (TILs) from a patient experiencing rapid recurrence under PD-1 blockade. Our analysis identified elevated expression of the ZFP36 family of RNA-binding proteins within exhausted CD8+ T cells (Tex cells) in this progressing tumor. The ZFP36 family is known to destabilize target mRNAs by binding to AU-rich elements in their 3' untranslated regions (3' UTRs). In EL4 T cells, Zfp36 overexpression accelerated the decay of the effector cytokine mRNAs Tnf, Il2, and Ifng, thereby impairing cytokine production. This process is exacerbated by hypoxia. Furthermore, high ZFP36 family expression correlates with poor prognosis in ICI-treated patients in a public bulk tumor transcriptomic dataset. These findings suggest that tumor microenvironment (TME)-induced hypoxia upregulates the ZFP36 family in Tex cells, which in turn suppresses cytokine production via post-transcriptional regulation, potentially contributing to impaired antitumor effector function.

Keywords:  PD‐1 blockade; T cell exhaustion; ZFP36 family; hypoxia; post‐transcriptional regulation

DOI:  https://doi.org/10.1111/cas.70546
Front Immunol. 2026 ;17 1984763

Correction: Stem-like CD4 T cells in tumors: an emerging framework for antitumor immunity.

Jiaxiang Xu, Yunchao Yang, Jun Zhang, Yue Zhang.

  [This corrects the article DOI: 10.3389/fimmu.2026.1853163.].

Keywords:  T cell differentiation; T cell stemness; TCF1; cancer immunotherapy; immune checkpoint blockade; stem-like CD4 T cells; tumor immunity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1984763
Curr Protoc. 2026 Oct;6(10): e70445

Investigating CD8 T Cell Exhaustion in Chronic LCMV Infection by Flow Cytometry.

Dominique Stark, Marie-Elen Tuchel, Gautier Stehli, Alessandro Genovese, Isaak Quast, Annette Oxenius.

  CD8 T cells and the process of T cell exhaustion are central topics in both basic immunology and translational research, including clinical applications. Here, we provide a comprehensive, step-by-step guide to investigate CD8 T cells in murine in vivo lymphocytic choriomeningitis virus (LCMV) infection models. We outline viral stock preparation, infection, and viral titer evaluation. We put an emphasis on flow cytometry as a method to investigate phenotypical and functional characteristics of CD8 T cell exhaustion, but the protocols provided will also facilitate imaging or transcriptomic analyses. With these resources, we aim to streamline establishment of the LCMV model for new users and to support harmonization and optimization of workflows for laboratories already working with this model. © 2026 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Virus production Basic Protocol 2: Virus titer quantification from virus stocks by focus-forming assay Alternate Protocol 1: Virus titer quantification from infected tissues by focus-forming assay Basic Protocol 3: Peptide-MHC-I tetramer production Basic Protocol 4: Naïve CD8 T cell isolation using StemCellTM kit Alternate Protocol 2: Naïve CD8 T cell enrichment using MojoSortTM kit Basic Protocol 5: Adoptive CD8 T cell transfer and LCMV infection Basic Protocol 6: Animal husbandry Basic Protocol 7: Preparation of single-cell suspension from secondary lymphoid organs Alternate Protocol 3: Preparation of single-cell suspension from peripheral tissues Basic Protocol 8: Extracellular and intracellular staining Basic Protocol 9: Restimulation analysis Basic Protocol 10: Sorting.

Keywords:  CD8 T cell exhaustion; LCMV; adoptive cell transfer; chronic viral infection; high‐parameter flow cytometry

DOI:  https://doi.org/10.1002/cpz1.70445
Cell Mol Immunol. 2026 Sep 30.

CAR signaling instructs divergent metabolic reprogramming and functional fates in αβ and γδ T cells.

Xiomar E Bustos, Leticia Tordesillas, Elena Martinez Planes, Miguel G Fontela, Sebastian Snedal, Renata Ariza Marques Rossetti, Victoria Izumi, Bin Fang, John M Koomen, Eric A Welsh, Patrick Hwu, Daniel Abate-Daga.

  γδ T-cell-based immunotherapies have become relevant as alternatives to conventional αβ T-cell products, with preclinical data demonstrating tumor burden reduction and the mitigation of tumor-induced tissue damage. Given that most CAR constructs have been optimized for αβ T cells, we hypothesized that distinct T-cell types may require tailored CAR architectures to achieve optimal function. To test this hypothesis, we conducted a systematic comparative analysis of γδ and αβ T cells transduced with a second-generation PSCA-targeting CAR (PSCA-8t28z). We found that although γδ and αβ CAR-T cells exhibit comparable levels of cytotoxicity, they differ phenotypically. Through a system-level phosphoproteomic analysis, we identified 307 phosphosites whose abundance differed between γδ and αβ CAR-T cells. Pathway enrichment analysis placed glycolysis/gluconeogenesis and TCR signaling within the top significantly overrepresented signaling networks. The results of functional validation studies confirmed that γδ CAR-T cells have lower glycolytic and oxidative phosphorylation capacity than αβ-CAR-T cells do and weaker activation of activator protein 1 (AP-1). Notably, we identified thioredoxin-interacting protein (TXNIP) as a potential actionable target to enhance γδ CAR-T-cell metabolism. Finally, we designed a new synthetic costimulatory receptor that potentiates AP-1 activation, resulting in improved in vivo persistence. These results highlight the fundamental biological differences between γδ and αβ T cells and support the development of cell type-specific receptor engineering strategies to maximize γδ CAR-T-cell function and therapeutic benefit.

Keywords:  AP-1 transcription factor; PSCA CAR-T cell; RANKL; TXNIP; c-Jun

DOI:  https://doi.org/10.1038/s41423-026-01475-y
Neuron. 2026 Sep 28. pii: S0896-6273(26)00681-1. [Epub ahead of print]

Peripheral CXCR3 blockade mitigates T cell infiltration and neurodegeneration in a mouse model of tauopathy.

Joshua T Emmerson, Hao Hu, Vivek Savani, Peter Lin, Mina Rohde, Prabal Sharma, Wade Self, Yongyi Li, Jonathan Nulman, Megan E Bosch, Zhe Liu, Javier Remolina Serrano, Xin Bao, Carla M Yuede, Mehdi Jorfi, Rudolph E Tanzi, Jason D Ulrich, David M Holtzman.

  Chemokine receptor CXCR3 mediates T cell recruitment into inflamed tissues, but its role in tauopathies is unclear. Here, we show that hippocampal injection of interferon-γ (IFNγ) acutely triggers CXCL10 upregulation and brain parenchymal T cell infiltration. Genetic deletion or antibody-mediated blockade of CXCR3 prevented IFNγ-induced T cell infiltration. In a mouse model of tauopathy and neurodegeneration, chronic systemic anti-CXCR3 treatment markedly reduced parenchymal CD4+ and CD8+ T cell accumulation, attenuated neurodegeneration, and improved aspects of cognition. CXCR3 blockade decreased microglial MHC-II expression without broadly suppressing classical disease-associated inflammatory phenotypes. Single-cell RNA sequencing and flow cytometry further revealed a reduction in the proportion of activated CD4+ T cell populations and elevated CD8+ T cell terminal exhaustion in the brain. These findings identify CXCR3-dependent chemotaxis as a critical signaling pathway for subtypes of T cells linked to tau-mediated neurodegeneration and highlight CXCR3 blockade as a potential disease-modifying therapeutic strategy for tauopathies.

Keywords:  CXCL10; CXCR3; T-lymphocyte; adaptive immunity; inflammation; neurodegeneration; tauopathy

DOI:  https://doi.org/10.1016/j.neuron.2026.08.030
J Immunother Cancer. 2026 Sep 29. pii: e015104. [Epub ahead of print]14(9):

IL-2/CD25 acts within the tumor microenvironment to reprogram tumor-specific cytotoxic CD8+ T cells while restraining regulatory T-cell accumulation.

Kathryn M LaPorte, Janika Põder, Daria Ivanova, Molly Dalzell, Paolo Serafini, Alejandro V Villarino, Thomas R Malek.

   BACKGROUND: Targeting the high-affinity interleukin-2 receptor (IL-2R) on CD8+ T effector cells elicits potent antitumor responses that are augmented when co-administered with programmed cell death protein 1 (PD-1) blockade.
METHODS: Using the mouse IL-2/CD25 fusion protein (mIL-2/CD25) at a high dose (HD) and anti-PD-1 checkpoint blockade, with the CT26 and MC38 colon carcinomas as models, the current study investigated how antitumor responses occurred when regulatory T cells (Tregs) are also a target of HD mIL-2/CD25. Single-cell RNA sequencing (scRNA-seq) and T-cell receptor (TCR) repertoire analysis of tumor-associated immune cells were used to identify how combination therapy reshaped the tumor microenvironment (TME). These data were cross-referenced with published datasets to (1) corroborate TCR specificity and (2) identify how CD8+ T-cell differentiation is affected by different IL-2/PD-1 strategies.
RESULTS: Here, we show that effective antitumor immunity by the combination therapy is a result of HD mIL-2/CD25-dependent reprogramming of CD8+ tumor-specific T cells that increases their function and supports their expansion within the TME, the latter also shaped by PD-1 blockade. This therapy supports antitumor responses by chemokines and inflammatory cytokines that selectively favor the migration of CD8+ T cells but not Tregs deep within the tumor. After HD mIL-2/CD25 treatment, Tregs within the TME showed impaired downstream IL-2R signaling, reflected by failed upregulation of forkhead box P3 and CD25, impaired development into effector Tregs, and enhanced cell death, the latter which likely offsets Treg proliferation. Many similarities were noted after direct comparison of these scRNA-seq findings with another study where IL-2 activity was targeted to PD-1+ CD8+ T cells. Notably, HD mIL-2/CD25 and anti-PD-1 combination promotes effector and 'stem-like' CD8+ T-cell subsets, perhaps even to a greater extent than the PD-1-targeted IL-2 strategy.
CONCLUSIONS: The efficient differentiation of exhausted CD8+ T cells into highly functional cells and the resulting potent antitumor responses by HD mIL-2/CD25 plus anti-PD-1 suggest that this approach may augment durable response rates more than currently achieved with checkpoint blockade monotherapy.

Keywords:  Immune Checkpoint Inhibitor; Immunotherapy; T cell; T regulatory cell - Treg; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2026-015104
Adv Sci (Weinh). 2026 Sep 27. e77992

A Multi-Targeting Chimeric Antigen Receptor-T Cell Platform to Overcome Antigen Heterogeneity in the Treatment of Non-Small Cell Lung Cancer.

Lina Wang, Yanlei Zhang, Shuixiu Peng, Chenchen Hou, Huaqi Guo, Tianyu Zhou, Alex H Chang, Lifeng Yan, Weining Xiong.

  Chimeric antigen receptor (CAR)-T cell therapy for solid tumors is limited by antigen heterogeneity and T cell exhaustion. To address these limitations, we develop a novel multi-targeting "Bicephali" CAR-T platform featuring a dual-transmembrane protein with two distinct extracellular antigen-binding domains and a shared intracellular 4-1BB co-stimulatory/CD3ζ signaling domain. CD276 and NKG2D ligands (NKG2DLs) show high and heterogeneous expression in non-small cell lung cancer (NSCLC) and are undetectable in normal tissues. Bicephali CAR-T cells targeting CD276 and NKG2DLs demonstrate superior tumoricidal activity against NSCLC than conventional BB002 CAR-T cells in vitro and in vivo, together with improved immunological synapse formation and mitochondrial metabolic fitness. In homogeneous NSCLC models co-expressing CD276 and NKG2DLs, Bicephali CAR-T cells achieve prolonged survival outcomes compared to monospecific CAR-T cells. In antigenically heterogeneous NSCLC, Bicephali CAR-T cells more consistently control tumors and prolong survival, whereas monospecific CAR-T cells fail to eliminate tumors following antigen loss. Mechanistically, improved mitochondrial fitness and antioxidant capacity in Bicephali CAR-T cells are associated with sustained T cell function, preserved stem-like differentiation, and durable effector responses. These findings support a multi-targeting CAR-T approach to address antigen heterogeneity in NSCLC and potentially other solid tumors.

Keywords:  CAR‐T cells; CD276; NKG2D ligands; NSCLC; antigen heterogeneity; bicephali

DOI:  https://doi.org/10.1002/advs.77992
NPJ Autoimmun. 2026 ;1(1): 4

Type 1 diabetes SIRPG risk variants increase SIRPγ expression and CD47 loss enhances CD8+ T cell cytotoxicity.

Robert C Sharp, Matthew E Brown, Leeana D Peters, Rhonda Bacher, Laura M Jacobsen, Todd M Brusko.

  Type 1 diabetes (T1D) risk variants within SIRPG influence transcript splicing and alter the expression of signal regulatory protein gamma (SIRPγ) on human T cells; however, the functional consequences of the risk variants remain poorly defined. Here, we demonstrate that peripheral blood mononuclear cells from individuals carrying a T1D-associated risk haplotype exhibit increased membrane-bound SIRPγ and reduced expression of its ligand CD47 across CD4+ and CD8+ T cell subsets compared to a protective haplotype. To interrogate the impact of impaired CD47 signaling, we generated CRISPR/Cas9 knockout (KO) models in Jurkat and primary human CD8+ T cells, as well as a pancreatic β-cell line (βLox5). CD47-deficient T cells displayed heightened activation, reduced co-inhibitory receptor expression, and increased production of IL-2 and TNF following stimulation. Furthermore, CD47 KO CD8+ T cell avatars expressing an HLA-A*02:01-restricted, IGRP265-273-reactive T cell receptor (TCR) exhibited enhanced cytotoxicity toward βLox5 targets, while CD47 KO βLox5 cells were more susceptible to apoptosis. These findings reveal that CD47 signaling constrains T cell effector function and β-cell susceptibility, and its disruption through altered SIRPγ-ligation may contribute to autoimmune pathogenesis in T1D.

Keywords:  Cell biology; Diseases; Immunology

DOI:  https://doi.org/10.1038/s44483-026-00002-5
Methods Mol Biol. 2027 ;3087 3-14

Multiparametric Flow Cytometry Analysis of Naïve, Memory, and Effector T-Cells.

Chih-Hsiung Chen, Pradeep K Dagur, Ankit Saxena.

  Polychromatic flow cytometry enables the detection and characterization of markers that are helpful in defining the phenotype of various cell subsets. Here, we described a flow cytometry-based method to characterize the phenotype of naïve, memory, and effector T cells. Being able to differentiate these cells is crucial in understanding immune response and immune profiling. Naïve T cells enable the body to fight off new, unrecognized infections and diseases, and Memory T cells are enriched for response to recall antigens. Furthermore, the antigen-experienced T-cell populations can be broadly divided into effector and memory cell compartments, which are needed to sustain a responsive immune system. Simplistically, the effector T cells require active antigenic stimulation to eliminate pathogens. On the other hand, Memory T cells are described as cells that remain present without antigenic stimulation and can expand rapidly upon secondary challenges. Recently, with the identification of central and effector memory T-cell subsets, tremendous effort has been devoted to characterize markers on the surfaces of these cells. Though various markers have been used to identify the subsets, no single marker that segregates one subset from the other has been described. Thus, multiple markers are needed to subset the cells in order to characterize them. Here we report the verification of a nine-color panel (CD3, CD4, CD8, CD45RO, CD28, CD95, CCR7, Live/Dead Aqua, Dump channel-CD19, CD14, CD56, CD16) that can successfully identify six distinct CD4 and CD8 T-cell populations within the naïve and effector cell subsets from human donors.

Keywords:  Immunophenotyping; Memory T cells; Multicolor-flow cytometry; Naïve T cells; T cells; Whole blood

DOI:  https://doi.org/10.1007/978-1-0716-5607-5_1
Mol Med. 2026 Aug 19. pii: 163. [Epub ahead of print]32(1):

NETs drive CD4⁺ T cell dysfunction in sepsis via mitochondrial ROS and impaired calcium signalling.

Hongru Li, Xuan Wang, Keran Sun, Jiachao Wang, Jiao Li, Enhao Zhang, Xiaoqing Li, Changwei Su, Zixin Li, Yushan Lin, Miao Li, Xiurong Wang, Hong Zhang, Chenhui Li, Lin Wei, Cuiqing Ma.

   BACKGROUND: Sepsis is a life-threatening condition with high mortality, in which sepsis-induced immunosuppression-characterized by CD4+ T cell dysfunction and apoptosis-worsens clinical outcomes. The mechanistic link between neutrophil extracellular traps (NETs) and CD4+ T cell fate in sepsis remains poorly elucidated.
METHODS: We integrated plasma analysis from 50 sepsis patients and 31 healthy controls, a murine cecal ligation and puncture (CLP) sepsis model, and in vitro assays with Jurkat cells and primary CD4+ T cells. We investigated the effects of NETs on CD4+ T cell calcium signaling and mitochondrial function, and verified the therapeutic efficacy of DNase I combined with the mitochondrial-targeted antioxidant mitoTEMPO.
RESULTS: Circulating NETs were significantly elevated in sepsis patients, positively correlated with disease severity (SOFA score) and negatively correlated with peripheral CD4+ T cell counts. NETs disrupted intracellular calcium homeostasis by inhibiting store-operated calcium entry, suppressing calcineurin activity and NFAT nuclear translocation, thus impairing T cell activation and IL-2 production. Additionally, NETs induced mitochondrial dysfunction via excessive mitochondrial reactive oxygen species (mtROS) production and reduced mitochondrial calcium uptake, leading to loss of mitochondrial membrane potential, structural damage, and subsequent CD4+ T cell apoptosis. In CLP mice, monotherapy with either DNase I or mitoTEMPO partially attenuated CD4+ T cell injury, while the combination significantly improved 7-day survival compared with monotherapy or vehicle, reduced plasma organ injury markers, and alleviated splenic lymphocyte apoptosis.
CONCLUSION: The NETs-mtROS axis represents an important pathway driving CD4+ T cell death in sepsis. Dual targeting of NETs and mitochondrial oxidative stress holds promising therapeutic potential for ameliorating sepsis-induced immunosuppression.

Keywords:   CD4 + T cells ; Immunosuppression ; Mitochondrial dysfunction ; NETs ; Sepsis

DOI:  https://doi.org/10.1186/s10020-026-01607-0
Front Immunol. 2026 ;17 1963310

Metabolic dysfunction and GZMK+ CD8+ T-cell remodeling in hepatocellular carcinoma: an evidence-stratified, hypothesis-generating review.

Qianqian Zhong, Wanruo Lyu, Jieying Li, Yiming Song, Yunxin Huang, Chunbin Wang, Juling Ji.

  Type 2 diabetes mellitus and metabolic dysfunction associated steatotic liver disease contribute to the growing burden of hepatocellular carcinoma, yet their effects on hepatic antitumor immunity remain incompletely defined. Recent single-cell and spatial profiling studies indicate that hepatocellular carcinoma contains diverse CD8+ T cell states, including cytotoxic, exhausted, tissue-resident, progenitor-like, and transitional phenotypes. This review synthesizes evidence linking hyperglycemia, insulin resistance, lipotoxic injury, chronic inflammation, fibrosis, altered antigen presentation, stromal remodeling, chemokine signaling, and nutrient availability to CD8+ T-cell remodeling in HCC arising in the context of metabolic dysfunction. Particular attention is given to GZMK+ CD8+ T cells, which may reflect non-terminal differentiation, inflammatory adaptation, or transitional immune states rather than conventional cytotoxic effector function. Although GZMK-high CD8+ T cell populations have been reported in hepatocellular carcinoma and therapy-associated immune contexts, direct evidence that type 2 diabetes induces these cells in the liver remains limited. This review specifically examines GZMK+ CD8+ T-cell states within the immunometabolic context of HCC, distinguishes direct hepatic and tumor evidence from extrapolated findings in metabolic liver disease and other inflammatory conditions, and proposes a testable framework for phenotypic, spatial, and functional validation. Integrated single-cell, spatial, protein level, T cell receptor clonality, functional, and clinical studies are needed to define their biological significance and translational value.

Keywords:  CD8+ T cells; GZMK; hepatocellular carcinoma; immunometabolism; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1963310
Adv Sci (Weinh). 2026 Sep 30. e77518

Macrophage Trogocytosis of Tumor Cells Drives the Immunosuppression of Tumor Microenvironment.

Chao Liang, Jiaqi He, Wan-Ru Zhuang, Yao Lei, Yanru Jiang, Xianbin Ma, Pan Liu, Zhujun Jiang, Yongheng Li, Hai-Yan Xie.

  Despite considerable advances in cancer immunotherapy, the persistent immunosuppressive tumor microenvironment (TME) seriously limits its performance in solid tumors. Here, we reveal that trogocytosis-an intercellular membrane transfer process-between tumor-associated macrophages (TAMs) and cancer cells serves as a critical mechanism driving this immunosuppression. We demonstrate that trogocytosis efficiency, inversely correlated with tumor cell cortical stiffness, varies substantially across cancer types and dictates immunosuppressive intensity through upregulation of CXCL5 and Arg-1, leading to CD8+ T cell exhaustion. Importantly, this mechano-immunological axis is conserved in humans, as evidenced by study with human cell lines and a strong correlation between trogocytosis markers and T cell exhaustion in clinical patient samples. Increasing tumor cell stiffness with simvastatin effectively suppressed trogocytosis, reversed T cell dysfunction, and synergistically enhanced the efficacy of adoptive T cell therapy. These findings establish macrophage trogocytosis as a fundamental driver of immunosuppressive heterogeneity and highlight its targeting as a promising strategy to potentiate cancer immunotherapy.

Keywords:  T cell exhaustion; cortical stiffness; immunosuppressive heterogeneity; trogocytosis; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/advs.77518
bioRxiv. 2026 Sep 22. pii: 2026.01.07.698250. [Epub ahead of print]

Age-associated Autoimmunity Driven by T cell Immunosenescence.

Ethan C McCarthy, Maryamsadat Seyedsadr, Madison F Bang, Caitlyn L H Pham, Christian Bustillos, Isabela Salazar, Ivan A Salladay-Perez, Jason K Whitmire, Christopher Fu, Sophie Blanc, Mehdi Bouhaddou, Jocelyn Weng, Faranak Fattahi, Melissa G Lechner, Perry Shieh, Anthony J Covarrubias, Maureen A Su.

While certain autoimmune conditions are more common in the young (e.g. Type 1 Diabetes), others are more frequent in the aged. A striking example is chronic inflammatory demyelinating polyneuropathy (CIDP), a CD4+ T cell-mediated autoimmune disease of the peripheral nervous system, which has a peak decade of onset of 70-79 years. How aging predisposes to autoimmunity, however, remains unclear. CD4+ T cells are highly susceptible to age-associated changes, including acquisition of immunosenescent features such as enhanced SA-β-gal activity, increased Cdkn1a (p21) expression, and upregulation of Tnfsf8 (CD153). We show here that CD4+ T cells exhibiting these changes are increased in CIDP patients and mice with CIDP-like disease. These CD4+ T cells exhibit a senescence-associated secretory phenotype (SASP), show functional senescence (i.e., decreased proliferation and resistance to apoptosis), and have enhanced capacity for inciting neuropathy. Notably, a senescent cell-clearing senolytic agent (fisetin) decreased the pathogenic capacity of CD4+ T cells, and a SASP-suppressing senomorphic therapy (ruxolitinib) protected mice against autoimmune demyelination. Together, these findings delineate a key role for age-associated senescent CD4+ T cells in driving age-associated autoimmunity.

DOI: https://doi.org/10.64898/2026.01.07.698250
Cancer Discov. 2026 Sep 29.

Spatially confined IL-12 programs CAR-NK through mTORC1 to coordinate antitumor immune networks.

Mubin Tarannum, Khanhlinh Dinh, Mila Stanojevic, Maily Nguyen, Marco Campisi, Andreia Maia, Fuguo Liu, Shaobo Yang, Grace C Birch, Eden Bobilev, Ian Gillanders, Michal Sheffer, Shikha Gupta, Junning Wang, Suthakar Ganapathy, Daniel E Michaud, Guillermo Nicolas Dalton, Seema Chugh, Quang-De Nguyen, Cloud P Paweletz, Prafulla C Gokhale, Yang Gao, Jose Cancelas, Jennifer L Guerriero, Toni K Choueiri, David A Barbie, Andrew J Aguirre, Rebecca L Porter, Ursula A Matulonis, John Koreth, Catherine J Wu, Robert J Soiffer, Jerome Ritz, Jianzhu Chen, Rizwan Romee.

Solid tumors evade immunotherapy because of immunosuppressive microenvironments that limit immune cell persistence and function. Although interleukin-12 (IL-12) potently activates antitumor immunity, its clinical use has been constrained by systemic toxicity. Here we engineered a CAR natural killer (NK) cell platform that integrated IL-12 signaling to enhance antitumor immunity. IL-12 signaling synergized with CAR activation to sustain mTORC1 activity through convergent Ras-ERK and PI3K pathways, promoting metabolic fitness, autonomous expansion, and sustained effector function. IL-12 also activated bystander NK cells, T cells, and macrophages to remodel the tumor microenvironment. To improve safety, IL-12 was tethered to a collagen-binding A3-domain, restricting its activity to the extracellular matrix and limiting systemic exposure. In ovarian and pancreatic cancer models, matrix-anchored IL-12 CAR NK cells expanded without exogenous cytokines and achieved durable tumor control. These findings suggest that mTORC1-mediated integration of CAR and cytokine signaling can enhance immune fitness and overcome immunosuppressive tumor microenvironments.

DOI: https://doi.org/10.1158/2159-8290.CD-26-0509
Front Immunol. 2026 ;17 1917932

Thy1 retroviral reporters: a versatile platform for congenic background-independent adoptive transfer and CD8+ T cell differentiation studies.

Chunlong Liu, Chunling Liu, Jing Zhong, Xiaodi Yang, Dapeng Wang.

  Adoptive T cell transfer remains a fundamental technique for dissecting the molecular mechanisms governing T cell differentiation. A successful adoptive-transfer experiment typically relies on labor-intensive construction of specific congenic mouse strains to distinguish donor from host cells. This limitation may be addressed by a readily detectable surface reporter. Thy1 is a candidate, but it remains unclear whether it is a reliable reporter for monitoring adoptively transferred CD8+ T cell differentiation because Thy1 is a functional protein involved in thymic development and cell activation. To address this question, we systematically evaluated the reliability, stability, and functional neutrality of Thy1.1 and Thy1.2, two Thy1 isoforms, as adoptive-transfer reporters during CD8+ T cell differentiation in vivo. Our results show that endogenous Thy1 expression remains stable across the differentiation stages examined. In the experimental settings tested, exogenous Thy1 reporter expression did not measurably alter the assessed differentiation phenotypes or donor-cell recovery. We further constructed and validated a Thy1 reporter-based platform that captured phenotypes associated with both loss-of-function (shRNA) and gain-of-function (cDNA) modulation of the transcription factor T-bet. This system provides a practical option for congenic background-independent adoptive transfer and genetic studies of CD8+ T cell differentiation.

Keywords:  CD8+ T cell differentiation; T-bet; adoptive transfer; retroviral vector; thy1

DOI:  https://doi.org/10.3389/fimmu.2026.1917932
J Cell Immunol. 2026 ;8(2): 65-73

Understanding the Mechanistic Connection between Dysbiosis and Polyamine Regulation in Oral and Intestinal Inflammation- Role of Tregs and Th17 Cells.

Pushpa Pandiyan.

Periodontitis and inflammatory bowel disease (IBD) are chronic inflammatory conditions driven by dysbiotic microbial communities that subvert host mucosal immunity. Central to the immunopathology of both diseases is the disruption of the balance between regulatory T cells (Tregs) and T helper 17 (Th17) cells, an equilibrium that governs tissue homeostasis versus inflammatory destruction. Polyamines, principally putrescine (PUT), spermidine (SPD), and spermine (SPN), are emerging as critical immunometabolic regulators that modulate the plasticity and functional identity of both cell populations. Dysbiosis, particularly the enrichment of microbial communities that drive aberrant polyamine biosynthesis through ornithine decarboxylase (ODC)-dependent pathways, generates a polyamine-rich microenvironment that further dysregulates T cell function and promotes sustained inflammation. Experimental evidence demonstrates that mucosal polyamine levels correlate with dysbiosis, dysfunctional Treg (TregDys) expansion, and CD4+CD4+T cell hyperactivation, collectively contributing to and perpetuating chronic inflammation. The striking parallels between periodontitis and IBD reinforce the existence of conserved mechanisms linking mucosal dysbiosis to polyamine-driven immune dysregulation, with shared therapeutic implications for targeting the dysbiosis-T cell-polyamine axis to restore immune homeostasis. This review presents a unified mechanistic framework connecting oral and intestinal dysbiosis, polyamine dysregulation, and disruption of the Treg/Th17 balance, linking both diseases along the oral-gut axis.

Keywords: Inflammatory bowel disease; Intestinal inflammation; T cells
Cell Rep Med. 2026 Sep 26. pii: S2666-3791(26)00527-6. [Epub ahead of print] 103110

Potentiating immunotherapy in "immune-cold" solid tumors through orchestrating T cell immunity via tumor-specific genetic engineering.

Jiaqi He, Chunguang Zhang, Chao Liang, Wenchi Xue, Yongheng Li, Lili Dai, Chunyuan Liu, Wan-Ru Zhuang, Xianbin Ma, Ran Cheng, Yao Lei, Weidong Nie, Hai-Yan Xie.

DOI: https://doi.org/10.1016/j.xcrm.2026.103110
Cancer Cell. 2026 Oct 02. pii: S1535-6108(26)00425-3. [Epub ahead of print]

Chemotherapy enhances cancer vaccine efficacy and expands stem-like TCF1+CD8+ T cells.

Laurine Noblecourt, Amanda Wicki, Ashwin Jainarayanan, Vinnycius Pereira-Almeida, James McAuliffe, Emily Steffke, Silvia Panetti, Hannah Fuchs, Ramiro A Ramirez-Valdez, Vineethkrishna Chandrasekar, Yanshu Cai, Sanne Boekestijn, Adrian V S Hill, Audrey Gerard, Marij J P Welters, Sjoerd H Van der Burg, Isabela Pedroza-Pacheco, Benoit J Van den Eynde, Carol Sze Ki Leung.

  Therapeutic cancer vaccines are increasingly tested in clinical settings alongside standard-of-care treatments that often include chemotherapy, yet whether chemotherapy synergizes with cancer vaccines remains unclear. Here, we tested heterologous prime-boost viral vector vaccines in combination with various chemotherapy regimens. Both carboplatin plus paclitaxel (CarboTaxol) and cyclophosphamide improve vaccine efficacy and enhance antigen-specific CD8+ T cell responses. These chemotherapies act as immunological adjuvants independently of tumor presence. Mechanistically, CarboTaxol induces an early, antigen-independent expansion of stem-like T cell factor 1 (TCF1)+CD8+ T cells, an effect also observed in patients with different cancer types. Genetic or pharmacological disruption of TCF1 impairs the immunological adjuvant effect of CarboTaxol. Adding programmed cell death 1 (PD-1) blockade to viral vector vaccines and CarboTaxol further improves tumor control and survival. Together, these findings identify a TCF1-dependent mechanism underlying the immune adjuvant effect of chemotherapy and provide a rationale for clinical evaluation of this triple combination therapy.

Keywords:  T cells; TCF1; anti-PD-1; cancer vaccines; chemotherapy; immune adjuvant; immunotherapy

DOI:  https://doi.org/10.1016/j.ccell.2026.09.006
J Control Release. 2026 Sep 30. pii: S0168-3659(26)00827-8. [Epub ahead of print] 115423

OX40 ligand-engineered dendritic cell nanovesicles potentiate antitumor immunity through dual-mode T cell activation.

Zhongqian Yang, Yiting Ding, Ying Yang, Chuyuan Deng, Xin Yin, Tong Yu, Jonathan Ma, Qiong Long, Yanbing Ma.

  The efficacy of classical dendritic cell (DC)-based cancer vaccines is limited by poor in vivo stability, inefficient lymph node delivery, and the immunosuppressive tumor microenvironment. Here, we developed a nanovaccine platform by engineering DC-derived nanovesicles (NVs) and established a membrane-anchoring strategy based on a recombinant cytolysin A (ClyA) fusion protein that efficiently inserts OX40 ligand (OX40L) from the extracellular side onto the surface of mature DCs and their derived NVs. The resulting E7-OX40L-NV, loaded with HPV16 E7 peptide, retained native and modified DC membrane proteins, exhibited efficient migration to draining lymph nodes, and showed good biocompatibility. In vitro, E7-OX40L-NV directly activated both naive and antigen-experienced antigen-specific CD8+ T cells and induced cytotoxic function. After uptake by DCs, the vesicles transferred peptide-MHC (pMHC) and OX40L to the DC surface, indirectly enhancing CD8+ T cell responses. In therapeutic TC-1 tumor models, E7-OX40L-NV induced potent antitumor immunity, including enhanced T cell effector function, reduced regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), increased intratumoral infiltration of functional T cells, remodeled T cell proliferation and exhaustion dynamics, and increased formation of long-lived memory precursor effector cells (MPECs), leading to significant tumor suppression and complete regression in a proportion of mice that rejected contralateral tumor rechallenge. Co-delivery of OX40L and antigen on the same NV was more effective than a physical mixture, underscoring the importance of spatial coordination. This ClyA-mediated membrane functionalization strategy provides a versatile tool for engineering cell-derived vesicles, and OX40L-engineered DC nanovesicles offer a promising platform for developing next-generation personalized cancer vaccines.

Keywords:  Antitumor immunity; Dendritic cells; Nanovesicles; OX40 ligand; T cell activation

DOI:  https://doi.org/10.1016/j.jconrel.2026.115423
Front Immunol. 2026 ;17 1935435

Metabolic licensing and restriction of innate immunity in the tumor microenvironment.

Ji Min Shin, Hye Yeon Choi, Jihyoun Kim, Seon Ah Lim.

  Tumor progression is driven by metabolic remodeling that generates a microenvironment characterized by nutrient deprivation, hypoxia, lactate accumulation, lipid dysregulation, and oxidative stress. These conditions affect innate immune populations, including natural killer (NK) cells, dendritic cells (DCs), macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs), shaping their activation, persistence, and functional states. Although many studies have defined metabolic pathways that regulate innate immune function in cancer, these findings are often discussed at the level of individual pathways or individual cell types, obscuring shared principles by which the tumor microenvironment controls innate immunity. Here, we use the concepts of metabolic licensing and metabolic restriction to describe how metabolic capacity and environmental constraints interact to shape innate immune function. Metabolic licensing refers to context-dependent metabolic states that provide sufficient bioenergetic and biosynthetic capacity to support sustained antitumor effector function, whereas metabolic restriction describes conditions in which nutrient limitation, mitochondrial dysfunction, redox imbalance, or suppressive metabolites constrain or progressively erode these functions. Rather than representing fixed binary states, licensing and restriction can occur along a continuum shaped by cell identity, signal duration, and local tumor conditions. We discuss how metabolic licensing and restriction shape antitumor and immunosuppressive innate immune populations, examine the stress-sensing pathways that connect environmental cues to innate immune fate, and summarize therapeutic strategies aimed at restoring metabolic fitness or alleviating metabolic restriction. Considering innate immune responses in terms of metabolic licensing and restriction helps explain how shared metabolic pressures within tumors can impair effector cells while supporting suppressive innate populations and may inform the development of immunometabolic approaches to cancer therapy.

Keywords:  immunometabolism; innate immunity; metabolic licensing; metabolic restriction; metabolic stress; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1935435
Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2606579123

α-aminobutyric acid promotes tumor progression by polarizing macrophages through the ASNS-mTORC2 axis.

Fei Li, Xiaorong Xie, Tongran Xu, Yu Tang, Yuting Xia, Yali Tang, Shijie Yuan, Mengdi Zhu, Xuwei Wu, Lan He, Shu-Hai Lin, Ran He.

  Tumor-associated macrophages (TAMs), the most abundant immune cell subset in the tumor microenvironment (TME), exhibit phenotypic plasticity and exert critical roles in tumor progression and antitumor immunity. Targeting TAM polarization has emerged as a promising strategy for cancer immunotherapy, yet the key regulators governing this process remain incompletely defined. Here, we identified α-aminobutyric acid (AABA) as a pro-tumor metabolite that drives M2-like polarization of TAMs to promote tumor progression. Mechanistically, AABA binds to asparagine synthetase (ASNS), reinforcing the mTORC2-IRF4 signaling axis to reprogram TAMs, switching macrophage metabolism from glycolysis to oxidative phosphorylation, a hallmark of pro-tumor M2-like phenotypes. Moreover, tumor-derived AABA was transported into macrophages by monocarboxylate transporters 1 and compromised the therapeutic efficacy of PD-1 checkpoint inhibition. Collectively, our findings uncover AABA as a previously unrecognized signaling metabolite to control TAM polarization, providing insights into the metabolic crosstalk within the TME and offering a potential therapeutic target to improve cancer immunotherapy outcomes.

Keywords:  asparagine synthetase; mTORC2; macrophage; tumor microenvironment; α-aminobutyric acid

DOI:  https://doi.org/10.1073/pnas.2606579123
iScience. 2026 Oct 16. 29(10): 117527

A systematic transcriptomic atlas and predictive framework for metabolite-driven T cell state transitions.

Yiyang Xu, Yiheng Zhao, Sizhe Yang, Huimin Li, Xiangrong Diao, Qianqian Zhang, Shuting Yu, Shuai Wang, Fangying Jiang, Qiang Wang, Yuhua Ma, Bo Jiao, Yun Tan, Yabin Liu.

  Gut microbial and endogenous metabolites are key regulators at the interface of host metabolism and immunity, yet their global effects on human T cell states remain poorly defined. Here, we profile primary human T cell responses to 364 endogenous and microbiota-derived metabolites using high-throughput digital RNA with perturbation of genes sequencing (DRUG-seq), revealing structured transcriptional trajectories spanning baseline, metabolically primed, and highly activated states. We develop DRUG-seq-PerturbFormer, a multi-task deep learning framework that quantitatively captures perturbation magnitude and directionality across these states. This analysis identifies a subset of metabolites that robustly reprogram T cell transcriptional programs. In a dextran sulfate sodium (DSS)-induced colitis model, representative candidates attenuated disease severity and were associated with suppression of inflammatory programs and partial restoration of immune homeostasis. Collectively, these findings show that metabolites act as signals shaping T cell function via transcription, nominating immunomodulatory targets for inflammatory diseases.

Keywords:  DRUG-seq; T cell; metabolites; perturbation atlas; predictive framework

DOI:  https://doi.org/10.1016/j.isci.2026.117527
Clin Immunol. 2026 Sep 29. pii: S1521-6616(26)00118-X. [Epub ahead of print] 110780

TIGIT regulates CD8+T cell exhaustion via the PI3K/AKT-FOXO1-TOX axis in extrahepatic cholangiocarcinoma.

Ruiheng Luo, Ling Li, Dehong Tan, Ping Zheng, Yu He, Qianfei Zuo, Tengqian Tang.

  Extrahepatic cholangiocarcinoma (ECCA) is an aggressive malignancy with poor prognosis and few treatment options, partly due to CD8+T cell exhaustion in the tumor microenvironment. The role of TIGIT in driving this process remains mechanistically unclear. Using patient-derived immunocompetent cultures (iPDCs), we show that TIGIT blockade in ECCA reverses exhaustion by downregulating TOX and restoring TCF-1. In mouse CD8+ T cells, transcriptomic analysis identifies the PI3K/AKT-FOXO1 axis as a critical mediator. Mechanistically, TIGIT suppresses AKT phosphorylation, leading to FOXO1 nuclear translocation, where FOXO1 directly binds the TOX promoter and activates its transcription. Together, these findings establish the TIGIT-PI3K/AKT-FOXO1-TOX axis as a core pathway driving CD8+T cell exhaustion in ECCA, filling a key mechanistic gap and offering new therapeutic targets for immunotherapy.

Keywords:  Extrahepatic cholangiocarcinoma; FOXO1; T cell exhaustion; TIGIT; TOX

DOI:  https://doi.org/10.1016/j.clim.2026.110780
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2026 Aug;34(4): 1226-1229

[Research on the Immunotherapy of T Cell Exhaustion in Multiple Myeloma --Review].

Ya Nan Cai, Xu Zhang Lu, Min Zhou.

  Multiple myeloma (MM) has strong heterogeneity and is still an incurable tumor. The new immunotherapy represented by bispecific antibody (BsAb) and chimeric antigen receptor T-cell immunotherapy (CAR-T) has shown significant efficacy in MM treatment. However, these therapies directly utilize T cell activity, and the efficacy is affected by the functional state of T cells. T cell exhaustion (Tex), one of the important characteristics of MM, is closely related to the progression, drug resistance, recurrence, and poor prognosis of MM. Therefore, Tex is the key factor limiting the efficacy of BsAb and CAR-T technologies. This article reviews the latest research progress on the mutual influence between Tex and these therapies.

Keywords:  T cell exhaustion; multiple myeloma; immunotherapy; bispecific antibody; chimeric antigen receptor T-cell immunotherapy

DOI:  https://doi.org/10.19746/j.cnki.issn1009-2137.2026.04.044
Cancer Sci. 2026 Sep 28.

INHBB Promotes Colorectal Cancer Progression by Inducing CD8+ T Cell Exhaustion via the ACVR2B-SMAD Signaling Axis.

Guanghui Liu, Yuanhua Liu, Hongchao Zhao, Junfeng Sun, Hongwei Yang, Qingqing Ding.

  To investigate the expression pattern, biological functions and regulatory mechanisms of inhibin beta B (INHBB) in colorectal cancer (CRC), and to clarify its role in mediating CD8+ T cell exhaustion via the INHBB-ACVR2B-SMAD signaling axis for identifying a novel therapeutic target in CRC targeted immunotherapy, we analyzed the expression profile and prognostic value of INHBB in CRC tissues using The Cancer Genome Atlas database. Stable INHBB knockdown and overexpression CRC cell lines were constructed, and the malignant phenotypes were evaluated by Transwell assays, flow cytometry and other functional experiments. The interaction between INHBB and ACVR2B was verified by co-immunoprecipitation and immunofluorescence, and the in vivo regulatory effects of this pathway were determined using mouse xenograft tumor models combined with SMAD inhibitors. INHBB was upregulated in CRC tissues and associated with poor prognosis. Functional assays demonstrated that INHBB promoted the proliferation and invasion and suppressed the apoptosis of CRC cells. Mechanistically, INHBB bound to ACVR2B on CD8+ T cells, activated SMAD signaling, and triggered CD8+ T cell exhaustion, whereas blockade of the SMAD pathway reversed INHBB-mediated immunosuppression and tumor progression. Collectively, INHBB dually regulates the malignant phenotypes of CRC cells and CD8+ T cell function through the INHBB-ACVR2B-SMAD axis, and targeting this axis may represent a promising therapeutic strategy for CRC immunotherapy.

Keywords:  CD8+ T cell exhaustion; INHBB; SMAD signaling pathway; colorectal cancer; tumor immune microenvironment

DOI:  https://doi.org/10.1111/cas.70542
Front Immunol. 2026 ;17 1963773

Immune remodeling of tumor-draining lymph nodes: mechanistic determinants of checkpoint blockade responsiveness.

Caiyan Jia, Shuxuan Li, Muhua Chen, Wuxia Yang, Yanqi Song, Aidi Wang, Baoshan Liu.

  Remodeling of tumor-draining lymph nodes (tdLNs) can precede overt nodal metastasis and has emerged as a determinant of immune checkpoint blockade (ICB) responsiveness. Sustained lymphatic delivery of tumor-derived antigens, extracellular vesicles, cytokines, and metabolites perturbs stromal and vascular programs, including lymphatic expansion, high endothelial venule dysfunction, and disruption of fibroblastic reticular cell (FRC) networks, with downstream impairment of antigen presentation and T-cell priming. Metabolites such as lactate and adenosine further promote tolerogenic antigen-presenting cell states and increase the activation requirements of tumor-reactive T cells. These changes are predicted to reduce the availability of TCF1+ progenitor-exhausted CD8+ T cells (Tpex), an ICB-responsive reservoir that sustains clonal expansion during PD-1/PD-L1 blockade. The Review links tdLN structural, cellular, and metabolic remodeling to ICB response and resistance, highlights reinforcement of regulatory circuits after metastatic colonization, and discusses translational strategies that incorporate tdLN functional state into therapeutic design, including restoration of type 1 conventional DC (cDC1) competence, metabolic co-targeting, neoadjuvant sequencing, adoptive use of tdLN-derived T cells, and biomarker-guided planning of local therapies.

Keywords:  TPEx; dendritic cell cross-presentation; immune checkpoint blockade; lymph node stromal remodeling; tumor-draining lymph nodes

DOI:  https://doi.org/10.3389/fimmu.2026.1963773
J Mol Cell Cardiol. 2026 Sep 28. pii: S0022-2828(26)00153-7. [Epub ahead of print]

Immune responses following myocardial infarction in aged mice.

Ebram Tharwat Melika, DiyaaElDin Ashour, Marc Appel, Daphne Steder, Panagiota Arampatzi, Thorsten Bischler, Lisa Popiolkowski, Ulrich Hofmann, Stefan Frantz, Gustavo Campos Ramos.

  Aging is a major risk factor for cardiovascular diseases and is often accompanied by systemic alterations of the immune system, such as the accumulation of terminally differentiated T cells, clonal hematopoiesis of intermediate potential, and dysregulated production of pro-inflammatory cytokines. However, how the aging immune system impacts post-myocardial infarction (MI) repair remains poorly understood. In the present study, we compared the post-MI inflammatory responses in 2- and 18-month-old C57BL/6 J mice of both sexes and monitored the distribution of interferon-gamma (IFN-γ) producing cells in these conditions using Ifng-YFP reporter mice. Our results show a conserved IFN-γ production signature both in mice and humans during physiological aging. In mice, the aging myocardium exhibited increased pro-inflammatory gene expression signature with increased recruitment of IFN-γ-expressing T cells following MI. Moreover, while this age-related inflammation had little impact in the acute post-MI responses, a persistent IFN-γ-production signature observed in elderly mice was associated with an aggravation of chronic adverse cardiac remodeling. Taken together, our results indicate that age-related smoldering inflammation may fuel the long-term progression of ischemic heart failure.

Keywords:  Aging; Heart failure; Interferon gamma; Myocardial infarction; T cells

DOI:  https://doi.org/10.1016/j.yjmcc.2026.09.008
Cell Death Dis. 2026 Sep 26. pii: 835. [Epub ahead of print]17(1):

Galectin-3 restrains T cell-driven inflammation in the testis and epididymis.

Hiba Hasan, Kimberly Jandel, Eva Wahle, Gabriela Michel, Linda Kreyling, Vishnu Kumar, Tara Procida-Kowalski, Sudhanshu Bhushan, Michaela Frolikova, Jens Rosellen, Thorsten Diemer, Katerina Komrskova, Marek Bartkuhn, Martin Speckmann, Hans-Christian Schuppe, Daniela Fietz, Christiane Pleuger, Andreas Meinhardt, Monika Fijak.

Galectin-3 (Gal-3) is a pleiotropic molecule involved in immune regulation and tissue homeostasis. While it has been implicated in reproductive tissue function, its role in shaping immune cell dynamics within the testis and epididymis remains incompletely defined. Here, we investigated the function of Gal-3 in the testis and epididymis under steady-state and inflammatory conditions, to determine its contribution to inflammatory responses and tissue damage. In both murine and human tissues, Gal-3 frequency and staining intensity increased along the testicular-epididymal axis, with the highest proportion of Gal-3+ cells in the cauda epididymidis, where it was detected across multiple murine immune cell populations, as well as epithelial and germ cells. Consistent with this distribution, Gal-3 deficiency reshaped the local immune landscape, leading to reduced macrophage populations and increased T cell abundance in the testis and cauda epididymidis. In a model of experimental autoimmune epididymo-orchitis (EAEO), Gal-3-deficient (Lgals3-/-) mice exhibited exacerbated inflammation, fibrosis, and irreversible organ damage, accompanied by increased T cell frequencies among CD45+ cells. Transcriptomic analysis revealed enhanced T cell activation signatures, particularly involving IFN-γ-related pathways. Functionally, Gal-3-deficient T cells showed increased cytokine production, specifically IFN-γ, which was further amplified in the presence of Gal-3-deficient macrophages, which in turn acquired a pro-inflammatory phenotype. Together, these findings identify Gal-3 as a key regulator of T cell activity and macrophage polarization with prominent effects in the testis and epididymis, with implications for understanding immune-mediated infertility.

DOI: https://doi.org/10.1038/s41419-026-09304-w
bioRxiv. 2026 Sep 24. pii: 2026.09.18.752092. [Epub ahead of print]

Refinement of the Pathogenic T Cell Receptor Motif Suggests Type 17 CD8+ T Cells Initiate HLA-B*27-associated Autoimmunity.

Isabel Risch, Qingping Wu, Rahul Devkota, Sophia Y Li, Joy Um, Tertuliano Alves Pereira Neto, Sarah Walden, Paulo Henrique Arantes de Faria, Andrei Belean, Lucy Durham, Michael Tang, Zoya Qaiyum, Robert D Inman, Leonie S Taams, Xinbo Yang, Philip A Mudd, Nicholas C Borcherding, Malachi Griffith, Obi L Griffith, Michael A Paley.

Human leukocyte antigen B*27 (HLA-B*27) is a major risk factor for autoimmune diseases such as axial spondyloarthritis (axSpA), acute anterior uveitis (AAU), and psoriatic arthritis (PsA). HLA-B*27 presents bacterial and self-antigens to disease-associated CD8+ T cells, however, how this leads to a pathogenic IL-17-mediated disease remains unclear. We performed mutational experiments in an established disease-associated TCR and demonstrated that the pathogenic motif encompasses a wider range of TCR sequences than previously appreciated. We next leveraged computational pairing of alpha/beta TCR sequencing (TCR-seq) to demonstrate that the broadened pathogenic motif distinguishes axSpA and AAU patients from healthy controls. Paired single-cell RNA sequencing and single-cell TCR sequencing datasets demonstrated that the pathogenic cells have a distinct transcriptional signature. We find a coupling of pathogenic TCRs to this transcriptional signature in public datasets from axSpA and PsA joint fluid and AAU ocular fluid. Finally, we detect the pathogenic CD8+ T cells in the gut and demonstrate that they express a Type 17 program. Our findings suggest that HLA-B*27+ axSpA, AAU, and PsA are initiated by HLA-B*27-restricted pathogenic CD8+ T cells that undergo Type 17 differentiation in response to intestinal antigens.
One Sentence Summary: Multiple HLA-B*27-associated autoimmune diseases share the same pathogenic CD8+ T cells with Type 17 gene expression and cytokine production.

DOI: https://doi.org/10.64898/2026.09.18.752092
bioRxiv. 2026 Sep 07. pii: 2026.09.03.749250. [Epub ahead of print]

A positively selected microRNA controls a reversible aging program in striated muscle.

Melissa A Boldridge, Lei Xu, Xiaoyin Wang, Michael Stirm, Gracia Bonilla, Chi Zhu, Justin Y Lee, Rachelle L Stark, Sneha Damal Villivalam, Marianne Bengtson Løvendorf, Andreas Petri, Alexandre Wagschal, Caslin Gilroy, Federico Gonzalez, Lei Cai, Peter I Hecker, Mogens Vyberg, Rahul Almeida, Chaitanya Punnati, Christopher Jin, Theresia M Schnurr, Dominique O Riddell, John C W Hildyard, Bachuki Shashikadze, Andreas Lange, Nikolai Klymiuk, Thomas Fröhlich, Sakari Kauppinen, Richard J Piercy, Joshua W Knowles, Alexander Fay, Sona Kang, Ryan E Temel, Ruslan I Sadreyev, Eckhard Wolf, Matthew L Springer, Anders M Näär.

Aging is the primary risk factor for most chronic diseases and is characterized in striated muscle by progressive functional decline, mitochondrial dysfunction, and chronic inflammation. The miR-128-1 locus resides within a positively selected haplotype on chromosome 2q21.3 associated with variation in grip strength, pulmonary function, and cardiometabolic traits in humans. Here, we show that antisense oligonucleotide-mediated inhibition of miR-128-3p restores muscle mass and function in aged mice, improves cardiac function while limiting adverse remodeling following myocardial infarction, and ameliorates skeletal and cardiac muscle pathology in mouse and pig models of Duchenne muscular dystrophy. Across these contexts, miR-128-3p inhibition induces a conserved transcriptional response characterized by activation of mitochondrial programs and suppression of inflammatory and fibrotic signaling, resembling the effects of established longevity interventions. These findings identify miR-128-3p as a regulator of a conserved aging-associated program and establish its inhibition as a strategy to restore tissue function across aging-related muscle pathologies.
Highlights: miR-128 loci associate with reduced grip strength; miR-128-1 also with lung function.miR-128-3p drives mitochondrial dysfunction and inflammation in striated muscle.Anti-miR-128 ASO rescues function in aged, infarcted, and dystrophic muscle.Inhibition recapitulates transcriptional effects of longevity interventions.

DOI: https://doi.org/10.64898/2026.09.03.749250