bims-imseme 2026-06-28 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–06–28
thirty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Metabolic alterations in the tumor microenvironment influence the anti-tumor immune function of CD8+ T cells via epigenetic modifications.
The transcription factor IRF8 drives tumor-specific exhaustion in CD8+ T cells.
AFF3 maintains metabolic quiescence in naïve CD8 T cells and prevents premature immune aging.
Mitochondrial Ca2+ signaling: A metabolic rheostat defining tumor and immune cell fate.
Single-cell gain-of-function mapping reveals latent regulatory programs governing CD8+ T cell fate.
Citrate Compartmentalization Controls Calcium-Dependent Cytokine Production in Effector T Cells.
Shared and context-specific mechanisms of T cell exhaustion in chronic viral infections and cancer: Transcriptional, metabolic, epigenetic, and therapeutic perspectives.
SIRPγ limits effector differentiation of human CD8 T cells in response to subthreshold TCR-signaling.
Cytotoxic lymphocyte heterogeneity in glioblastoma: insights from single-cell and spatial multiomics toward precision immunotherapeutic reprogramming.
Fate induction through asymmetric T cell division is modulated by chimeric antigen receptor costimulatory domains.
Double negative T cells decline in inflammatory reproductive dysfunction.
Targeting DGAT1 reprograms lipid landscape and restores CD8⁺ T cell immunity in pancreatic cancer.
Cell Cycle Sensing Shapes Human T Cell Fate and Exhaustion Programs.
Crosstalk between CD8+ T cells and systemic bile acid metabolism shapes antiviral immunity and immunopathology.
Immuno-cell metabolic changes in HIV-1 infection.
Author Correction: cBAF complex components and MYC cooperate early in CD8+ T cell fate.
Adenosine deaminase co-immunization reverses age-associated immunosenescence by restoring germinal center T follicular helper cell function.
A Healthy Lifestyle Can Slow Immune System Aging and Reduce Age-Related Chronic Inflammation: A Narrative Review.
Understanding the immune microenvironment of ovarian cancer.
CRISPR/Cas9-Mediated Gene Knockout Reveals a Nonredundant Role for p16INK4A in Controlling TCR-Dependent and Independent CD8 T Cell Expansion.
Decoding the immunometabolic landscape identifies SLC7A5 as a vulnerability in chemo-immunotherapy resistant TNBC.
Activation-induced SLC7A1 expression enhances T cell sensitivity to cGAMP-mediated STING signaling.
FDX1 Depletion Activates CD8+ T Cell Antitumor Immunity by Promoting DMBT1 Secretion in Cuproptosis of Colorectal Cancer.
Beyond a waste product: lactate as a master metabolite dictating anti-tumor T-cell fate.
cDC1s license CD8+ T cell-mediated neurodegeneration.
MAPK-activated protein kinase 2 orchestrates memory T-cell inflation in cytomegalovirus infection.
Paclitaxel Dosing Regimens Drive Differential CD4⁺ T Cell Responses in the Dorsal Root Ganglia and Modulate Neuropathic Pain Severity.
Human tissue-resident CD8 T cells contribute to trophoblast homeostasis in health and during acute inflammation.
The transcription factor Eomes drives a stemness program in CD4+ T cells that promotes anti-tumor immunity in response to immunotherapy.
UBE2F impedes CD8 T cell memory.
O-GlcNAcylation-mediated glycolytic reprogramming of CD4+ T cells contributes to type H vessel impairment in diabetic osteoporosis.
Stem-like precursors of exhausted Th cells upheld by a Tox-Myb-Eomes transcriptional hierarchy propagate Th cell responses in chronic infection.

Int Rev Immunol. 2026 Jun 27. 1-18

Metabolic alterations in the tumor microenvironment influence the anti-tumor immune function of CD8+ T cells via epigenetic modifications.

Yaru Liu, Wei Du, Weimin Deng.

  Metabolic reprogramming within the tumor microenvironment (TME) is a pivotal driver of CD8+ T cell dysfunction in cancer. Tumor cells outcompete T cells for essential nutrients, including glucose and amino acids, while accumulating immunosuppressive metabolites such as lactate and 2-hydroxyglutarate. Beyond direct functional impairment, emerging research reveals that these metabolic alterations orchestrate CD8+ T cell transcriptional programs by remodeling their epigenome-via histone modifications, DNA methylation, and non-coding RNA networks-thereby dictating their differentiation, cytotoxic potential, and memory formation. A deeper understanding of how TME-derived metabolic signals shape the epigenetic landscape of CD8+ T cells is crucial for improving current cancer immunotherapeutic strategies. This review systematically delineates how key TME metabolic features, including nutrient deprivation and oncometabolite accumulation, regulate CD8+ T cell fate through epigenetic pathways. Furthermore, we discuss promising therapeutic strategies that target the metabolism-epigenetics axis to reinvigorate CD8+ T cell anti-tumor immunity, offering novel perspectives for enhancing adoptive cell therapy and immune checkpoint blockade.

Keywords:  CD8+ T cells; Cancer immunotherapy; epigenetics; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.1080/08830185.2026.2687543
J Exp Med. 2026 Aug 03. pii: e20252115. [Epub ahead of print]223(8):

The transcription factor IRF8 drives tumor-specific exhaustion in CD8+ T cells.

Marco Ongaro, Romane Thouenon, Isaac Crespo, Alexandre Dumez, Mélanie Charmoy, Eduardo Roman Camacho, Victoria J Morel, Daniela Cropp, Emma Desponds, Giulio Zanette, Yi-Chuan Wang, Letizia Vergili, Laure Tillé, Inés Di Resta, Marine M Leblond, Jésus Corria Osorio, Ping-Chih Ho, Werner Held, Grégory Verdeil.

T cell exhaustion is a major obstacle to effective immunotherapy in cancer and chronic infection. Here, we identify the transcription factor IRF8 as a tumor-specific regulator of CD8+ T cell exhaustion. IRF8 is strongly expressed in tumor-reactive CD8+ T cells but not during chronic viral infection. Its expression is induced by TCR signaling and can be suppressed by type I IFN (IFN-I). Sustained IFN-I signaling, a hallmark of chronic infection, correlates with reduced chromatin accessibility at the Irf8 locus and progressive repression of Irf8 expression. In tumor-specific CD8+ T cells, IRF8 overexpression enhanced TOX expression while reducing IFNγ, granzyme B, and TNF production. Conversely, Irf8 deficiency diminished exhaustion, restored effector functions, and improved tumor control. Mechanistically, IRF8 directly binds the Tox locus and promotes its transcription. We further show that additional IRF-family transcription factors contribute similarly to the exhausted T cell program, identifying this transcriptional network as a key regulator of tumor-associated T cell dysfunction.

DOI: https://doi.org/10.1084/jem.20252115
JCI Insight. 2026 Jun 23. pii: e207387. [Epub ahead of print]

AFF3 maintains metabolic quiescence in naïve CD8 T cells and prevents premature immune aging.

Molly E Lumnitzer, Stefanie F Valbon, Stephanie A Condotta, Allison E Norlander, Sheng Liu, Jun Wan, Martin J Richer.

  It is necessary for naïve CD8 T cells to be actively maintained in a quiescent metabolic state in order to respond robustly to infection while avoiding inappropriate activation during homeostasis. With age this quiescent state is lost and the CD8 T cell response to infection decreases. The factors regulating metabolic quiescence of CD8 T cells and how this regulation is lost during aging are not completely understood. Herein, we identify the transcription factor AFF3 as a regulator of metabolic quiescence in naïve CD8 T cells. While naïve AFF3 deficient CD8 T cells are more metabolically active prior to infection, they have reduced accumulation in response to viral infection, and this is correlated with a poor capacity to engage glycolysis. During aging in both murine and human CD8 T cells, AFF3 expression is decreased. In mice, this is associated with a loss of metabolic quiescence and reduced capacity to accumulate following infection. Our data highlight the role of metabolic regulation in CD8 T cell quiescence and identifies a transcription factor that may be a target to reinvigorate CD8 T cell responses during aging.

Keywords:  Aging; Glucose metabolism; Immunology; Metabolism; Metabolomics; T cells

DOI:  https://doi.org/10.1172/jci.insight.207387
Trends Immunol. 2026 Jun 25. pii: S1471-4906(26)00137-7. [Epub ahead of print]

Mitochondrial Ca2+ signaling: A metabolic rheostat defining tumor and immune cell fate.

Amélie E Bura, Andrea Rolong, Christophe Paget, Maxime Guéguinou.

  Mitochondrial calcium (mtCa2+) has long been framed as a bioenergetic regulator, yet evidence redefines it as a relevant immunometabolic switch. Within the tumor microenvironment, the mitochondrial calcium uniporter (MCU) complex and the NCLX-TMEM65 efflux axis maintain a 'Goldilocks zone' of Ca2+ homeostasis. This can be exploited by cancer cells to sustain oxidative phosphorylation and tricarboxylic acid-derived oncometabolite production, including succinate, fumarate, and 2-hydroxyglutarate, while imposing ionic and nutrient constraints on infiltrating immune cells. Chronic mtCa2+ overload in effector T cells drives mitochondrial dysfunction and exhaustion, while oxidative phosphorylation-dependent Ca2+ flux enforces the acquisition of an immunosuppressive profile in macrophages. Disrupting these tumor-immune ionic imbalances through selective MCU modulation or efflux pathway targeting offers a strategy to restore immune surveillance and/or enhance immune checkpoint inhibitor therapies.

Keywords:  T cells; cancer; immune checkpoint blockade; immunometabolism; mitochondrial calcium signaling; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.it.2026.05.012
Res Sq. 2026 Jun 11. pii: rs.3.rs-9929244. [Epub ahead of print]

Single-cell gain-of-function mapping reveals latent regulatory programs governing CD8+ T cell fate.

J Justin Milner, Brandon Pratt, Genevieve Mullins, Nolan Brown, Lara van Rooyen, William Green, Fucong Xie, Vasyl Zhabotynsky, Jennifer Modliszewski, Nicholas de Vries, Alexander Jambor, Gabrielle Cannon, Jarred Green, Zaid Syed, Alec Plotkin, Andrew Kennedy, Coral Del Mar Alicea Paunto, Huitong Shi, Emily Merritt, Takeshi Egawa, Aswhin Somasundaram, Wei Wang, Jessica Thaxton, Gianpietro Dotti, H Kay Chung.

CD8⁺ T cells mediate host defense and tumor immunity through specialized differentiation states, yet the regulatory programs that guide these states may also limit their functional potential. Loss-of-function studies have defined many regulators required for T cell differentiation, but they do not readily reveal regulatory activities that emerge only when transcription factors are ectopically expressed outside their native lineage, dosage, or temporal context. Here, we developed single-cell gain-of-functon(GOF) sequencing (scGOF-seq), a multiplexed platform for in vivo mapping of transcription factor overexpression in antigen-specific CD8⁺ T cells across immunocompetent models of infection and cancer. By enforcing expression of canonical T cell regulators, lineage-silenced developmental factors, and temporally restricted transcription factors, scGOF-seq uncovered unexpected in vivo activities. Developmental regulators normally silenced in T cells, including NANOG, SOX2, OCT4 and GATA2, reshaped T cell differentiation in context-dependent ways, with NANOG promoting stemness-associated phenotypes and accumulation during chronic infection. In parallel, sustained cMyc expression outside its native temporal window generated a stem-like, effector-featured state with enhanced metabolic fitness, reduced terminal exhaustion, and profound antigen-dependent expansion exceeding 5,000-fold. Importantly, cMyc GOF maintained cell-cycle checkpoint signatures and demonstrated a strong dependence on antigen presence for proliferation across the tested conditions. scGOF-seq further identified cooperating transcription factor modules that complemented cMyc-driven programs and improved T cell responses in solid tumors. These findings establish systematic GOF perturbation as a framework for uncovering latent and temporally constrained regulatory activities in CD8⁺ T cells and guiding immune-state engineering.

DOI: https://doi.org/10.21203/rs.3.rs-9929244/v1
bioRxiv. 2026 Jun 12. pii: 2026.06.11.731694. [Epub ahead of print]

Citrate Compartmentalization Controls Calcium-Dependent Cytokine Production in Effector T Cells.

Andrea L Cote, Claire L McIntyre, Joshua A Acklin, Lillian R Delacruz, Yunping Qiu, Irwin J Kurland, Alison E Ringel.

Cytokine production is a core function of effector T cells, yet the mechanisms that regulate cytokine output during an immune response remain incompletely understood. Here, we identify citrate compartmentalization as a cellular mechanism by which CD8 + T cells couple cytokine production to glucose availability. Under glucose-replete conditions, citrate transport from the mitochondria to the cytosol by the citrate carrier SLC25A1 suppresses calcium-dependent transcription factor activity in effector T cells. Either reducing glucose availability or blocking the exchange of citrate across the mitochondrial membrane raises free cytosolic calcium, thereby driving nuclear localization of Nuclear Factor of Activated T cells (NFAT)-family transcription factors and sustaining cytokine production. As a calcium-chelating metabolite, we show that citrate buffers free cytosolic calcium, thereby linking calcium-dependent signaling to mitochondrial fuel oxidation. We also identify signatures of this regulatory mechanism across hundreds of human cancer cell lines, where there are negative associations between citrate-derived metabolites and calcium-dependent transcriptional programs, and within the spatial organization of human tumors. These findings identify cytosolic citrate as a broadly conserved metabolic rheostat coupling glucose availability to calcium signaling. By adding calcium signaling to the known functions regulated by SLC25A1, our work reveals a mechanism by which mitochondria adaptively tune cytokine expression and other calcium-dependent programs in response to local metabolic conditions, such as nutrients that are available within a tissue or tumor.

DOI: https://doi.org/10.64898/2026.06.11.731694
Cytokine Growth Factor Rev. 2026 Jun 21. pii: S1359-6101(26)00046-8. [Epub ahead of print]90 88-106

Shared and context-specific mechanisms of T cell exhaustion in chronic viral infections and cancer: Transcriptional, metabolic, epigenetic, and therapeutic perspectives.

Wencan Zhang, Weifeng Yuan, Congli Yuan, Yuqiang Cheng, Dandan Zhang, Xu Cao, Chan Ding.

  T cells are crucial for defending against viral infection and cancer by eliminating infected or transformed cells and establishing immune memory. However, persistent antigenic stimulation in chronic infections or tumors drives T cells into a dysfunctional state known as exhaustion. This state is characterized by reduced proliferation and effector functions, upregulation of inhibitory receptors like PD-1, LAG-3, and CTLA-4, and alterations in transcriptional, epigenetic, and metabolic programs. T cell exhaustion is driven by both intrinsic factors, including changes in transcription factor networks and metabolic dysfunction, and extrinsic factors, such as continuous antigen exposure and an immunosuppressive microenvironment. Key molecules like PD-1, TOX, and TCF-1 are central to this process, though the complex interactions between intrinsic and extrinsic signals in chronic viral infections and cancers remain poorly understood. This review summarized T cell exhaustion in chronic viral infections, such as HIV, HBV, and SARS-CoV-2, as well as in tumors, emphasizing shared mechanisms and context-specific differences. We focused on the roles of transcriptional networks, metabolic changes, immune checkpoints, and exhaustion-related signaling. Additionally, we discussed emerging therapeutic strategies, such as immune checkpoint inhibitors, CAR-T cell therapies, cytokine supplementation, and metabolic interventions, based on recent high-impact studies. By integrating insights from both chronic infection and cancer, this review aims to identify common principles of T cell exhaustion and propose strategies to improve clinical outcomes in chronic viral diseases and cancer immunotherapy.

Keywords:  CAR-T immunotherapy; Cancer; Immune memory; T cell exhaustion; T cell response; Viral infection

DOI:  https://doi.org/10.1016/j.cytogfr.2026.06.004
Immunohorizons. 2026 Jun 16. pii: vlag027. [Epub ahead of print]10(6):

SIRPγ limits effector differentiation of human CD8 T cells in response to subthreshold TCR-signaling.

Megan Morse, Xanthie Rodriguez, Erika Delarosa, Sierra Rodriguez, Juma Shanil, Sushmita Sinha.

  Signal regulatory protein gamma (SIRPγ) is a T cell-specific surface receptor in the human immune system with previously undefined function in human CD8 T cell differentiation. We report that SIRPγ expression varies substantially across individuals and stratifies CD8 T cell differentiation states. Individuals with low SIRPγ expression exhibit an increased frequency of CD27-CD45RO+ effector-like and CD27-CD45RO- terminally differentiated CD8 T cells, while high expressors retain a predominance of naïve and central memory cells. To investigate the functional role of SIRPγ, we performed small interfering RNA-mediated knockdown in naïve human CD8 T cells. Under suboptimal TCR stimulation, SIRPG knockdown drove robust effector-like differentiation marked by increased CD45RO expression, T-bet upregulation, and enhanced production of TNF-α, IFN-γ, and granzyme B. This phenotype was not recapitulated by CD47 blockade, indicating that SIRPγ modulates differentiation through a CD47-independent mechanism. These findings identify SIRPγ as a negative regulator of CD8 T cell effector programming under limiting stimulatory conditions. Interindividual variability in SIRPγ expression may influence immune homeostasis and susceptibility to immunopathology, highlighting SIRPγ as a potential therapeutic target in settings of dysregulated T cell responses.

Keywords:  SIRPγ; autoimmunity; differentiation; human T cells; inflammation

DOI:  https://doi.org/10.1093/immhor/vlag027
Front Immunol. 2026 ;17 1837084

Cytotoxic lymphocyte heterogeneity in glioblastoma: insights from single-cell and spatial multiomics toward precision immunotherapeutic reprogramming.

Wentao Dong, Yang Li, Zhuolin Wu, Quanlin Fu, Jinshuang Zhao, Bangyue Wang, Jia Yao, Chenglu Lu, Minfeng Tong.

  Glioblastoma (GBM) represents the most aggressive primary brain tumor in adults, characterized by a profoundly immunosuppressive tumor microenvironment (TME) that systematically disables cytotoxic lymphocyte function and renders conventional immunotherapy largely ineffective. While exhaustion of CD8+ T cells and natural killer (NK) cells within solid tumors has been extensively studied in other cancer types, the CNS-specific architectural, metabolic, and molecular constraints that shape cytotoxic lymphocyte heterogeneity in GBM remain insufficiently characterized. Recent advances in single-cell RNA sequencing (scRNA-seq) and spatial multiomics have begun to reveal a rich landscape of cytotoxic lymphocyte subpopulations in GBM. These include TCF-1+ progenitor-exhausted T cells (Tpex), terminally exhausted CD8+ T cells (Tex), and dysfunctional natural killer (NK) cell subsets, each distributed across anatomically distinct immune niches. This review synthesizes current knowledge across three interconnected areas: the single-cell atlas of GBM-infiltrating cytotoxic lymphocytes; the spatial organization of their dysfunction within perinecrotic, perivascular, and infiltrative-edge niches; and the epigenetic and transcriptional programs that underlie GBM-specific cytotoxic failure, including dysregulation of the TOX/TCF-1 axis and IDH-mutation-driven silencing of NKG2D ligands. Critically, we compare CD8+ T cell and NK cell exhaustion mechanisms, highlighting their mechanistic divergence and therapeutic implications. We further discuss how these multiomics insights can be translated into neurosurgically relevant strategies, including intraoperative tumor profiling, progenitor T cell expansion via epigenetic priming, NKG2A/TIGIT dual blockade, and intracavitary delivery of engineered NK cells. Together, this review proposes a spatially and cellularly resolved framework for understanding cytotoxic immune failure in GBM and outlines precision immunotherapy approaches tailored to the unique immunobiology of the CNS tumor microenvironment.

Keywords:  NK cell dysfunction; blood-brain barrier; cytotoxic lymphocytes; glioblastoma; immunotherapy; progenitor exhausted T cells; single-cell transcriptomics; spatial genomics

DOI:  https://doi.org/10.3389/fimmu.2026.1837084
Nat Immunol. 2026 Jun 22.

Fate induction through asymmetric T cell division is modulated by chimeric antigen receptor costimulatory domains.

Caitlin S Frazee, Sisi Chen, Corbett T Berry, Casey S Lee, Reid A Banciella, Lucianna Ngo, David Shon, Patrick J Herman, Jake S Fischman, Chloe L Leff, Anna Chen, Yvonne Kuo, Alexander A Shestov, Andre R Kelly, Bakir Valentic, Michael C Milone, Roddy S O'Connor, Christoph T Ellebrecht.

Chimeric antigen receptor (CAR) T cell therapy can result in impressive remissions in hematological malignancies, but relapse is common because a minority of infused cells acquire a long-lived, memory-like state. All US Food and Drug Administration-approved CAR T cell products incorporate either 4-1BB or CD28 costimulatory domains, each conferring distinct phenotypic outcomes, but how these signals control early fate decisions is incompletely understood. Here we show that costimulatory domains control memory fate acquisition through asymmetric cell division. CD28 CAR T cells have higher CAR surface expression and enhanced surface proteome asymmetry after the first division, yet paradoxically they show muted transcriptional, epigenetic and metabolic divergence between daughter cells, correlating with reduced long-term persistence. Conversely, 4-1BB CAR T cells have less surface polarization but more pronounced transcriptional, metabolic and epigenetic divergence, yielding proximal effector-prone and distal persistence-prone daughters. Integrating surface proteomics, transcriptomics, metabolomics and chromatin accessibility, we show how costimulatory domains tune asymmetric cell division to shape CAR T cell fate, providing a mechanistic foundation for optimizing cellular immunotherapy.

DOI: https://doi.org/10.1038/s41590-026-02548-w
Sci Rep. 2026 Jun 21.

Double negative T cells decline in inflammatory reproductive dysfunction.

Enitome E Bafor, Toni Martin, Bruna Karoline Tatematsu, Ian A Bettencourt, Adrienne E Kimmel, Dorothy K Sojka, Howard A Young.

  Double-negative T cells (DNTs; CD3+CD4-CD8-) have been implicated in immune regulation in autoimmune settings, but their relevance to reproductive tissue immune balance and inflammation-associated infertility remains unclear. Here, we define a population of TCRβ+NK1.1- DNTs enriched in the mouse ovary and uterus and profiled its phenotype, tissue behavior, and function in inflammatory models associated with impaired fertility. In parallel, we performed RNA-seq on spleen- and thymus-derived NK1.1- DNT and CD8+ T cell enriched population. Relative to CD8+ T cells, peripheral NK1.1- DN T-cell-enriched populations displayed an activated, regulatory-like transcriptional profile with reduced Cd8a/Cd8b1, Il7r, and cytotoxic effector markers, alongside increased expression of Pdcd1, Lag3, Tox, and Il10. Ex vivo, FACS-sorted splenic DNTs produced low inflammatory cytokine output after CD3/CD28 stimulation and suppressed CD8+ T-cell proliferation primarily through contact-dependent mechanisms. In vivo, ovarian DNTs decreased following CD8-targeting depletion, and ovarian and uterine DNTs showed limited exchange in parabiosis. In chronic interferon-γ-driven inflammation (ARE-/-) and zona pellucida 3-induced ovarian inflammation, reproductive tissues exhibited reduced DNT frequencies, a shift in the DNT: CD8+T ratio favoring CD8+ T cells and increased activated CD8+ phenotypes. Finally, adoptive transfer of ex vivo FACS-sorted wild-type DNTs into ARE-/- females increased pregnancy frequency, supporting DNT-associated immunoregulation as a feature of inflammation-associated infertility.

Keywords:  CD8+ T cells; Double-negative T cells; IFN-γ-mediated inflammation; Ovarian immune tolerance; Uterine immune tolerance

DOI:  https://doi.org/10.1038/s41598-026-57959-4
Nat Commun. 2026 Jun 25.

Targeting DGAT1 reprograms lipid landscape and restores CD8⁺ T cell immunity in pancreatic cancer.

Zhongkun Liu, Lang Chen, Tong Zhang, Yuliang Wang, Panpan Ma, Xiangwei Zhang, Ronghui Liu, Ruiying Zhang, Xuanhao Zhang, Qingqing Su, Jinyan Huang, Da Wang, Qi Zhang, Cunqi Ye, Yun-Hua Liu.

Lipid accumulation is a hallmark of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment, yet effective strategies to reprogram this lipid-rich niche and restore anti-tumor immunity remain limited. Here, we show that diacylglycerol O-acyltransferase 1 (DGAT1) as a tumor-intrinsic metabolic checkpoint that promotes immune evasion. DGAT1 inhibition rewires tumor lipid metabolism by promoting increased fatty acid uptake and redistribution, thereby depleting extracellular free fatty acids that impair CD8⁺ T cell function. Mechanistically, decreased palmitate availability alleviates endoplasmic reticulum stress, preserves FOXO1 activity, and supports stem-like CD8⁺ T cell differentiation. This competitive lipid remodeling enhances memory potential, restrains terminal exhaustion, and sensitizes PDAC tumors to PD-1 checkpoint blockade in vivo. Together, our findings identify tumor-immune lipid crosstalk as a key barrier to effective immunity in PDAC and establish DGAT1 as a promising therapeutic target to restore T cell function and improve immunotherapy response.

DOI: https://doi.org/10.1038/s41467-026-74315-2
bioRxiv. 2026 Jun 12. pii: 2026.06.11.731737. [Epub ahead of print]

Cell Cycle Sensing Shapes Human T Cell Fate and Exhaustion Programs.

Meelad Amouzgar, Tara Murty, Patricia Favaro, Elena Sotillo, Trevor Bruce, Daniel Ho, Avery J Lam, Robert Tibshirani, Crystal L Mackall, Sean C Bendall.

Cell cycle (CC) dynamics are reflected in diverse T cell processes such as TCR activation, expansion, contraction, differentiation, senescence, anergy, and exhaustion; linking CC behaviors to functional and dysfunctional T cell states in development and disease. Progression through CC checkpoints is also tightly linked to cell fate decisions across development. Yet, much remains unknown about the connection between CC sensing and T cell differentiation programs. To disentangle the relationship across T cell state, time-since-activation, receptor signaling, division, and CC, we leverage high-throughput single-cell mass cytometry for parallel measurement of these diverse biological states. By modulating CC progression and receptor signaling with inhibitors as well as tonic signaling Chimeric Antigen Receptor (CAR) models of T cell exhaustion, we reveal that earlier G1/S CC programs crosstalk with receptor signaling to control T cell fate, and that exhaustion programs are downstream to aberrant, S-G2 phase CC arrest signatures in tonic CAR signaling in vitro , in situ, and in vivo across human cancers in association with CD8 T-lymphocyte dysfunction.

DOI: https://doi.org/10.64898/2026.06.11.731737
JCI Insight. 2026 Jun 22. pii: e189882. [Epub ahead of print]11(12):

Crosstalk between CD8+ T cells and systemic bile acid metabolism shapes antiviral immunity and immunopathology.

Felix Clemens Richter, Zsofia Keszei, Csilla Viczenczova, Maximilian Baumgartner, Henrique G Colaço, Magdalena Siller, Lisa Holnsteiner, Hatoon Baazim, Anna Hofmann, Aubrey Burrett, Anna Schönbichler, Lukas Endler, Joel Xu En Wong, Laura Antonio-Herrera, Oleksandr Petrenko, Fabian Amman, Jakob-Wendelin Genger, Claudia D Fuchs, Hubert Scharnagl, Hanns-Ulrich Marschall, Thomas Reiberger, Karl S Lang, Clarissa Campbell, Michael Trauner, Andreas Bergthaler.

  Antiviral immunity profoundly impacts host metabolism, which can, in turn, modulate immune responses and influence disease pathology. The liver orchestrates systemic bile acid (BA) metabolism, a pathway disrupted in chronic liver diseases such as viral hepatitis. BAs are increasingly recognized for their immunomodulatory properties. Thus, improved understanding of the interplay between immunity and BA metabolism may reveal novel therapeutic avenues. Using lymphocytic choriomeningitis virus (LCMV) as a model, we investigated the interplay between chronic virus infection, BA metabolism, and immunity. Chronic LCMV infection increased BA levels and shifted circulating and liver BA composition toward host-derived, conjugated BAs. Hepatic BA transport and synthesis genes were broadly downregulated, in part depending on CD8+ T cells. Pharmacological inhibition of the main hepatic transporter of conjugated BAs, NTCP (Slc10a1), increased hepatic damage, while combined genetic disruption of the BA transporters Slco1a1, Slco1a4, and Slco1b2, responsible for the hepatic reuptake of unconjugated BA, reduced liver pathology and impaired antiviral CD8+ T cell responses. These findings reveal a reciprocal interplay between BA metabolism and CD8+ T cells, expanding our understanding of adaptive immunity in viral hepatitis. They also highlight how immunometabolic changes in liver disease may affect adaptive immune responses against infections.

Keywords:  Hepatitis; Hepatology; Immunology; Metabolism; T cells

DOI:  https://doi.org/10.1172/jci.insight.189882
Infect Dis Immun. 2025 Jul;5(3): 177-189

Immuno-cell metabolic changes in HIV-1 infection.

Linle Xu, Yufen Jiang, Xuexing Zheng, Hongbo Shi.

  Recent research has shown that metabolic processes within immune cells are essential for both human immunodeficiency virus 1 (HIV-1) infection and the immune response. Throughout HIV-1 infection-from acute stages to chronic infection and viral latency-immune cells experience shifts in energy demands and metabolic pathways, paralleling T-cell exhaustion. Dysregulated immune metabolism compromises immune cell function, leading to immune dysfunction and persistent inflammation. Therefore, metabolic alterations in immune cells constitute a critical mechanism in HIV-1 progression and chronic inflammation. This review specifically explores the metabolic profiles and roles of T cells, monocytes-macrophages, dendritic cells, natural killer cells, and B cells at different stages of HIV-1 infection, emphasizing the effects of HIV-1 on the metabolic pathways of diverse immune cell types. These insights offer valuable therapeutic strategies aimed at inhibiting viral replication, restoring immune function, and controlling disease progression.

Keywords:  DCs; Glycolysis; HIV-1; Metabolism; Monocyte–macrophages; T cells

DOI:  https://doi.org/10.1097/ID9.0000000000000159
Nature. 2026 Jun 24.

Author Correction: cBAF complex components and MYC cooperate early in CD8+ T cell fate.

Ao Guo, Hongling Huang, Zhexin Zhu, Mark J Chen, Hao Shi, Sujing Yuan, Piyush Sharma, Jon P Connelly, Swantje Liedmann, Yogesh Dhungana, Zhenrui Li, Dalia Haydar, Mao Yang, Helen Beere, Jason T Yustein, Christopher DeRenzo, Shondra M Pruett-Miller, Jeremy Chase Crawford, Giedre Krenciute, Charles W M Roberts, Hongbo Chi, Douglas R Green.

DOI: https://doi.org/10.1038/s41586-026-10813-z
bioRxiv. 2026 Jun 09. pii: 2026.06.04.730208. [Epub ahead of print]

Adenosine deaminase co-immunization reverses age-associated immunosenescence by restoring germinal center T follicular helper cell function.

Emily N Bitsko, David R Joyner, Jeffrey R Maslanka, Kyra Woloszczuk, Arden O Edgerton, Matthew R Bell, Christian Sell, Mohamad-Gabriel Alameh, Joris Beld, Elias K Haddad, Michael C Abt, Michele A Kutzler.

Older adults experience disproportionate morbidity and mortality from Clostridioides difficile infection (CDI); however, existing toxoid- and receptor binding domain (RBD)-based vaccines elicit suboptimal protection in aged hosts due to the age-associated defects in CD4 + T cell function, T follicular helper (T FH ) cell activation, and antibody quality. We evaluated whether adenosine deaminase (ADA), an enzymatic immune modulator that degrades immunosuppressive adenosine, and improves GC T FH differentiation and survival, could reverse these age-related impairments when co-delivered with DNA vaccine plasmids targeting toxin A and B RBDs (pRBD). In aged mice, pRBD vaccination alone produced markedly reduced toxin-specific effector/memory CD4 + T cells, diminished T FH activation, and poor toxin A neutralization compared to vaccinated young mice. Co-immunization with plasmid-encoded adenosine deaminase-1 (pADA) restored toxin-specific CD4 + T cell generation and cytokine production, activation-induced marker (AIM) T FH responses, and antibody-mediate toxin neutralization to levels comparable to young adults. Mechanistically, pADA co-immunization was associated with the reduction of CXCR4 on germinal center (GC) T FH cells-an age-related defect linked to impaired GC positioning and diminished B cell help-suggesting that ADA improves humoral quality by correcting GC T FH mislocalization. These immune enhancements corresponded with improved clinical outcomes in morbidity, mortality, and weight-loss following C. difficile spore challenge of aged mice. Finally, pADA significantly reduced adenosine levels in aged lymph nodes, implicating a potential enzymatic-based regulation of GC immunosenescence. Together, these findings identify ADA as a metabolic adjuvant capable of reversing key features of vaccine immunosenescence and highlight adenosine dependent CXCR4 regulation as a tractable axis for improving vaccine efficacy in older populations.

DOI: https://doi.org/10.64898/2026.06.04.730208
Int J Mol Sci. 2026 Jun 21. pii: 5605. [Epub ahead of print]27(12):

A Healthy Lifestyle Can Slow Immune System Aging and Reduce Age-Related Chronic Inflammation: A Narrative Review.

Marta Cąkała-Jakimowicz, Anna Domaszewska-Szostek, Monika Puzianowska-Kuźnicka.

  Age-related decline in immune system function is characterized by reduced numbers of naïve lymphocytes, the accumulation of senescent cells, impaired function of all immune cell types, and chronic low-grade inflammation (inflammaging). These alterations contribute to increased susceptibility to infections and malignancies, as well as to autoimmunity and other age-associated diseases. This article reviews current evidence on lifestyle interventions that may mitigate immune aging. Lifestyle-related strategies, including regular physical activity, nutritional interventions (e.g., different diets, caloric restriction, and other fasting-related approaches), stress reduction, and vaccination, are discussed as key modulators of immune function and systemic inflammation. Notably, vitamin D supplementation has been shown to reduce the incidence of autoimmune diseases by 22%. In comparison, caloric restriction has led to a decrease in CRP and TNF-α by 40% and 50%, respectively. Emerging complementary approaches, such as mind-body practices and controlled cold exposure, show promise, though current evidence remains limited and inconsistent. Therefore, integrated lifestyle strategies may slow aging-related immune decline and support healthy aging. However, longitudinal trials are required to define the optimal intervention parameters, population-specific thresholds, and the long-term durability of immune rejuvenation.

Keywords:  diet; immunosenescence; inflammaging; nutritional interventions; physical activity; stress reduction

DOI:  https://doi.org/10.3390/ijms27125605
Front Oncol. 2026 ;16 1837496

Understanding the immune microenvironment of ovarian cancer.

Meifeng Shen, Shuni Zhang, Yijun Zhu, Qiaoli He, Weiming Chen.

  Ovarian cancer remains the most lethal gynecological malignancy, yet immune checkpoint inhibitors (ICIs) demonstrate limited clinical efficacy due to profound CD8+- T cell exhaustion within a highly heterogeneous tumor immune microenvironment (TME). Single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of this complex ecosystem by resolving rare immune subsets, reconstructing lineage trajectories, and mapping dynamic intercellular signaling networks. Emerging single-cell atlases reveal that terminally exhausted T cells evolve from plastic progenitor populations, notably GZMK+- subsets, while ascitic fluid functions as a distinct immunomodulatory reservoir that continuously shapes intratumoral immune dynamics. Furthermore, multi-compartment transcriptomic profiling uncovers myeloid-lymphoid crosstalk that actively sustains localized immunosuppression and drives therapeutic resistance. These high-resolution molecular insights are increasingly leveraged to accurately predict ICI responsiveness, rationally design novel combinatorial regimens, and strategically guide next-generation adoptive cellular therapies. This review summarizes the scRNA-seq-driven advances in characterizing the ovarian cancer TME, emphasizing how single-cell resolution dismantles immunosuppressive barriers to T cell reinvigoration and establishes a robust translational framework for precision immunotherapy.

Keywords:  T cell exhaustion; chimeric antigen receptor T-cell therapy; immune checkpoint inhibitors; immune microenvironment; ovarian cancer; single-cell RNA sequencing

DOI:  https://doi.org/10.3389/fonc.2026.1837496
Eur J Immunol. 2026 Jun;56(6): e70224

CRISPR/Cas9-Mediated Gene Knockout Reveals a Nonredundant Role for p16INK4A in Controlling TCR-Dependent and Independent CD8 T Cell Expansion.

Silvia Fiori, Cecilia Adragna, Emilia Malvicini, Tommaso Basini, Donatella Galgano, Edoardo Scarpa, Sandra Jovic, Niklas A Schmacke, Veit Hornung, Federica Sallusto, Ludovica Bruno, Antonio Lanzavecchia, Manuel Albanese.

  The possibility of enhancing T cell function by deleting specific genes represents a long-sought goal in preclinical studies and ultimately for clinical applications. Using CRISPR/Cas9 genome editing, we report that, in human cytotoxic CD8 T cell clones, the cell cycle checkpoint gene CDKN2A, encoding p16INK4A, plays a nonredundant role in controlling T cell receptor (TCR)-dependent and independent cell expansion. Deletion of CDKN2A dramatically enhanced antigen-driven and homeostatic proliferation, while preserving effector functions. In contrast, the deletion of other cell cycle inhibitors (CDKN1B, CDKN2C, and CDKN2D), alone or in combination, had no impact on T cell proliferation. We also report that mediator complex subunit 12 (MED12) and the E3 ubiquitin ligase CBL-B deletions did not affect proliferative capacity of CD8 T cell clones. Interestingly, deletion of the negative regulator of Ras signaling, RASA2, increased antigen sensitivity and cytotoxic activity, while not improving in vitro expansion. Collectively, these findings reveal a unique and critical nonredundant role for p16INK4A in regulating CD8 T cells. Deletion of CDKN2A offers a promising strategy to enhance CD8 T cell expansion ex vivo, thereby improving TCR discovery pipelines and, potentially, therapeutic applications.

Keywords:  CD8 T cells; CRISPR/Cas9; cell cycle; cytotoxicity; gene editing; p16INK4A; proliferation

DOI:  https://doi.org/10.1002/eji.70224
Clin Exp Med. 2026 Jun 25.

Decoding the immunometabolic landscape identifies SLC7A5 as a vulnerability in chemo-immunotherapy resistant TNBC.

Sen Zhong, Bolin Yu, Shengyi Zhou, Wenlong Chen, Fanglong Liu, Huanhuan Zhu, Fang Min, Fengyuan Qian.

  Metabolic reprogramming within the tumor microenvironment (TME) limits the efficacy of chemo-immunotherapy in triple-negative breast cancer (TNBC). Despite advances in high-resolution profiling, the specific intercellular metabolic crosstalk driving immune evasion remains incompletely understood. Here, we present a comprehensive single-cell metabolic atlas of the TNBC ecosystem to decode spatial and cell-type-specific metabolic vulnerabilities. Our multidimensional analysis reveals a distinct paracrine metabolic communication axis: CXCL9+ macrophages upregulate rate-limiting enzymes (IDO1/2) to become a potential source of local kynurenine, which is subsequently imported by cytotoxic T cells. Through in vitro co-culture and in vivo models, we demonstrate that this kynurenine uptake triggers impaired effector function and phenotypic exhaustion. Crucially, pharmacological blockade of SLC7A5 with the specific inhibitor JPH203 abrogates this metabolic toxicity, restores T cell effector function, and enhances the anti-tumor efficacy of combined cisplatin and anti-PD-1 therapy. Collectively, our findings delineate the Kynurenine-SLC7A5 metabolic axis as a critical driver of immunosuppression, providing a compelling rationale for integrating amino acid transport blockade to overcome resistance to chemo-immunotherapy.

Keywords:  Chemo-immunotherapy resistance; Immunometabolism; Kynurenine; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10238-026-02231-2
Cell Rep. 2026 Jun 22. pii: S2211-1247(26)00658-3. [Epub ahead of print]45(7): 117580

Activation-induced SLC7A1 expression enhances T cell sensitivity to cGAMP-mediated STING signaling.

Valentino Sudaryo, Dayanne R Carvalho, Jacqueline A Carozza, Xujun Cao, Courtney Kernick, Anthony F Cordova, J Michelle Lee, Theodore L Roth, Lingyin Li.

  STING (stimulator of interferon genes) agonists are promising innate immune therapies and can be synergized with adaptive immune checkpoint blockade therapies for cancer treatment, but their effectiveness is limited by the toxicity to activated T cells. How STING agonists such as cGAMP and its analogs enter and induce STING activation and toxicity in T cells is unclear despite known transporters for other cell types. Here, we identify the cationic amino acid transporter SLC7A1 as a cGAMP transporter in activated primary mouse and human T cells. T cells upregulate this transporter upon activation to meet their high metabolic demand, but this comes at the cost of enabling increased transport and toxicity of cGAMP. We identified distinct residues in SLC7A1 that mediate cGAMP and arginine activity, suggesting that cGAMP transport may be separable from arginine uptake. These findings suggest that modulation of SLC7A1 may influence T cell susceptibility to cGAMP and its analogs.

Keywords:  ADU-S100; CP: immunology; CP: molecular biology; LRRC8A; LRRC8C; SLC7A1; STING; T cells; VRAC; arginine; cGAMP; extracellular cGAMP; toxicity

DOI:  https://doi.org/10.1016/j.celrep.2026.117580
Cancer Sci. 2026 Jun 26.

FDX1 Depletion Activates CD8+ T Cell Antitumor Immunity by Promoting DMBT1 Secretion in Cuproptosis of Colorectal Cancer.

Jieqiong Wu, Zaixi Lian, Mingzhou Li, Xingtu Qin, Xiaoyu Lei, Lihua Yang, Lin Bing, Qiuyue Li, Lingyan Zhou, Zhiyang Ma, Xuemei Xu, Jinghao Huang, Zilong Chen, Lijie Chen, Lingjie Zhang, Zhiyuan Xiao, Xiangyu Jian, Xiaoqin Zhang, Yanqing Ding, Yaping Ye, Li Liang, Hongli Jiao, Shuyang Wang.

  Cuproptosis, a copper-dependent form of regulated cell death, has been documented in colorectal cancer (CRC), yet its impact on the tumor immune microenvironment remains incompletely understood. Here, we demonstrate that elesclomol-induced cuproptosis potently activates innate and adaptive antitumor immunity, markedly enhancing CD8+ T cell cytotoxicity while attenuating exhaustion. Mechanistically, FDX1, which correlates inversely with CD8+ T cell infiltration and predicts poor prognosis, functions as a core regulator of CD8+ T cell functionality during cuproptosis. FDX1 promotes CRC proliferation and metastasis while suppressing CD8+ T cell cytokine production. We further show that FDX1 binds DICER1 to reduce DMBT1 mRNA stability, with FDX1 and DMBT1 expression exhibiting significant negative correlation in CRC tissues. Our findings establish the FDX1-DICER1-DMBT1 axis as a critical regulator of CRC progression and immune evasion, suggesting that therapeutic targeting of this pathway could enhance antitumor immunity and overcome resistance to existing immunotherapies.

Keywords:  CD8+ T cell; DMBT1; FDX1; colorectal cancer; cuproptosis

DOI:  https://doi.org/10.1111/cas.70457
Cell Death Dis. 2026 Jun 23.

Beyond a waste product: lactate as a master metabolite dictating anti-tumor T-cell fate.

Xiangyu Dai, Jingjia Chang, Siyue Wang, Lutterodt Bentum-Ennin, Jian Zhou, Xiaomin Zuo, Wanglai Hu.

Lactate, a key byproduct of tumor metabolic reprogramming, accumulates in the tumor microenvironment (TME) and profoundly shapes T cell-mediated anti-tumor immunity. As research into TME metabolism advances, lactate has emerged as a critical regulator with broad effects on immune function. In many cancers-including gastric cancer, hepatocellular carcinoma, lung cancer, melanoma, and pancreatic cancer-lactate suppresses or remodels anti-tumor immunity by acting on CD8⁺ T cells, regulatory T cells (Tregs), dendritic cells (DCs), and immune checkpoint molecules. The underlying mechanisms are becoming increasingly well-defined. However, major knowledge gaps remain, especially regarding how lactate-associated enzymes (e.g., LDHA), lactate transporters (e.g., MCT4), and signaling pathways impact T cell function. This review summarizes how lactate regulates anti-tumor immune responses and explores emerging immunotherapies targeting lactate metabolism, with a focus on metabolic enzymes and transporters. We cover preclinical and clinical progress on LDHA inhibitors and lactate transporter inhibitors. By comprehensively analyzing lactate's function in the TME, we aim to build a theoretical framework for precision tumor immunotherapy and propose future directions centered on modulating the immune microenvironment through lactate-targeted strategies.

DOI: https://doi.org/10.1038/s41419-026-08976-8
Nat Rev Immunol. 2026 Jun 22.

cDC1s license CD8+ T cell-mediated neurodegeneration.

Jonathan K Monteiro, Véronique E Miron.

DOI: https://doi.org/10.1038/s41577-026-01329-8
J Immunol. 2026 Jun 07. pii: vkag170. [Epub ahead of print]215(6):

MAPK-activated protein kinase 2 orchestrates memory T-cell inflation in cytomegalovirus infection.

Eleni Panagioti, Xueyang Yu, Yi Wen Kong, Kristina Macakova, Noe B Mercado, Sean Edward Lawler, Michael B Yaffe, Charles H Cook.

  Memory T-cell inflation is a distinctive immunological phenomenon observed during persistent viral infections such as cytomegalovirus (CMV). Unlike conventional memory T-cell responses, which contract after infection resolution, a subset of CMV-specific T cells undergoes a progressive and sustained expansion, termed "inflation", which is thought to be critical for long-term immune surveillance. The molecular mechanisms that govern memory T-cell inflation remain incompletely understood, yet they are pivotal for understanding immune persistence and designing strategies against chronic viral infections. In this study, we investigated the role of MAPK-activated protein kinase 2 (MK2), a key downstream effector of p38 MAPK signaling, in regulating T-cell responses during murine CMV (MCMV) infection. Using MK2 knockout (MK2-KO) mice, we demonstrate that MK2 deficiency alters the dynamics of MCMV-specific CD8+ T-cell responses without impairing viral control or tissue replication. MK2 deficiency led to a reduction in noninflationary MCMV-specific CD8+ T cells during acute infection, followed by enhanced expansion of inflationary CD8+ T-cell subsets during latent infection. Furthermore, MK2-KO mice exhibited impaired effector differentiation, as evidenced by decreased expression of the terminal differentiation marker KLRG1 on MCMV-specific CD8+ T cells. Collectively, these findings identify MK2 as an important regulator of CD8+ T-cell magnitude, kinetics, and phenotype during both acute and latent MCMV infection. By demonstrating a role of MK2 in the regulation of memory T-cell inflation, this study provides new mechanistic insight into immune regulation with implications for vaccination, chronic infection, and immune aging.

Keywords:  CD8+ T cells; KLRG1; MK2; cytomegalovirus; memory inflation

DOI:  https://doi.org/10.1093/jimmun/vkag170
bioRxiv. 2026 Jun 09. pii: 2026.06.05.730418. [Epub ahead of print]

Paclitaxel Dosing Regimens Drive Differential CD4⁺ T Cell Responses in the Dorsal Root Ganglia and Modulate Neuropathic Pain Severity.

Kenyah G N Ferreira, Moriah E Weese-Myers, Leslie S Bradford, Diana J Goode.

While chemotherapy is effective in killing cancer cells, its non-specific cytotoxicity harms peripheral neurons, leading to chemotherapy-induced peripheral neuropathy (CIPN). Lacking effective interventions, clinicians often reduce or discontinue treatment. However, these adjustments do not necessarily reverse neuropathy and may jeopardize cancer control. Growing evidence now indicates that chemotherapy not only exerts neurotoxic effects but also modulates immune responses. The degree to which chemotherapy dosing regimens shape CD4 + T cell responses in the dorsal root ganglia (DRG), and how these cells influence mechanical hypersensitivity, remains poorly understood. In this study, female mice were administered a single, high dose (sHD) or multiple low doses (mLD) of paclitaxel (PTX). The mLD group, which received the higher cumulative dose, exhibited an earlier T cell response in the DRG and attenuated mechanical hypersensitivity with fewer ATF3 + DRG neurons compared to the sHD group. This regimen promoted a focused CD4 + T cell response while driving a broad and diversified CD8 + T cell expansion. In contrast, the sHD PTX regimen elicited a delayed, polyfunctional CD4 + T cell response but generated limited CD8 + effector differentiation. To directly assess the contribution of CD4 + T cells to CIPN pathogenesis, we administered PTX to mice lacking CD4 + T cells. CD4 deficient mice were significantly less hypersensitive than CD4 + sufficient mice with a stronger reduction in the sHD group. Although higher cumulative doses are associated with increased CIPN risk, our results suggest that the concentration and frequency of PTX more directly influence DRG immune programming, and that this immune shaping modulates CIPN severity.

DOI: https://doi.org/10.64898/2026.06.05.730418
bioRxiv. 2026 Jun 09. pii: 2026.06.05.730192. [Epub ahead of print]

Human tissue-resident CD8 T cells contribute to trophoblast homeostasis in health and during acute inflammation.

Caitlin S DeJong, Marie Frutoso, Nicole B Potchen, Geervani Daggupati, Andrew J Konecny, Yin Huang, Manu Setty, Swati Shree, Stephen A McCartney, Martin Prlic.

Previous studies have highlighted that some T cell subsets in tissues can provide signals to support tissue cell homeostasis and differentiation. If and how T cell-tissue cell signaling is altered in healthy compared to inflamed tissues is poorly understood. Here, we address if communication between human T cells and tissue cells changes from steady state to an acutely inflamed state in the human placenta. We used single cell analysis strategies to examine invasive cytotrophoblasts (iCTBs) and immune cells isolated from third trimester healthy and acutely inflamed human placentas. We performed cell communication analysis to predict cell-cell communication networks, and found evidence that iCTBs provided signals to support the recruitment of T cells, as well as the formation of tissue-resident memory CD8 T cells (Trm). In exchange, Trm provide signals to support iCTB homeostasis. During acute inflammation, iCTBs and macrophages underwent profound transcriptional changes, while most T cell subsets only underwent limited transcriptional changes. This was not due to T cell exhaustion or tolerance, as T cells were functionally intact. Cell communication analysis and validation at the protein level provide evidence that T cells can maintain their homeostatic support to iCTBs during acute inflammation.

DOI: https://doi.org/10.64898/2026.06.05.730192
Immunity. 2026 Jun 24. pii: S1074-7613(26)00229-3. [Epub ahead of print]

The transcription factor Eomes drives a stemness program in CD4+ T cells that promotes anti-tumor immunity in response to immunotherapy.

Arantxa Agesta, Chloé Ferrand, Anne-Louise Le Dorze, Cindy Peillex, Nadège Carrié, Rebecca Barascud, Arthur Palak, Lucie Esteban, Tanguy Bernal, Emeline Joulia, Céline Colacios, Tania Margarido Pereira, Romain Peroceschi, Andrea Pichler, Adeline Chaubet, Margot Zahm, Abdelhadi Saoudi, Hicham El Costa, Veronique Adoue, Benjamin Y Lu, Liliana E Lucca, Ludovic Martinet, Anne S Dejean.

  CD4+ T helper (Th) cells contribute to tumor immunity, yet the subsets and differentiation programs involved remain unclear. Here, we show that the transcription factor Eomesodermin (Eomes) is essential for Th-mediated anti-tumor immunity. Eomes orchestrated the differentiation and maintenance of an exhausted-like Th cell lineage, transcriptionally and functionally distinct from conventional effector or memory Th subsets. This Eomes-dependent program was enhanced by 4-1BB stimulation and promoted effective Th-cell-mediated tumor control. The progenitor subset of this lineage (pTh) expressed stemness-associated transcription factors, displayed self-renewal capacity, and seeded effector subsets capable of controlling tumor growth. At the transcriptional level, Eomes supported the survival, metabolic fitness, and apoptotic resistance of this lineage. Eomes⁺ pTh cells exhibited conserved transcriptional features in humans across multiple tumor types. As the most expanded Th cell population upon immune checkpoint inhibitor therapy, targeting these cells has potential to improve current immunotherapies.

Keywords:  Th cells; eomes; exhaustion; immunotherapy; progenitors; tumor immunity

DOI:  https://doi.org/10.1016/j.immuni.2026.05.018
J Exp Med. 2026 Jul 06. pii: e20260995. [Epub ahead of print]223(7):

UBE2F impedes CD8 T cell memory.

Li Zhong, Hua Gu.

Long-term maintenance of immune memory is critical for the control of recurring virus infections and cancer. In this issue of JEM, Ma et al. (https://doi.org/10.1084/jem.20252687) report that the E2 ubiquitin-conjugating enzyme UBE2F restrains long-term CD8 T cell memory.

DOI: https://doi.org/10.1084/jem.20260995
Cell Signal. 2026 Jun 26. pii: S0898-6568(26)00349-9. [Epub ahead of print] 112694

O-GlcNAcylation-mediated glycolytic reprogramming of CD4+ T cells contributes to type H vessel impairment in diabetic osteoporosis.

Yujun Jiang, Yaling Dai, Xiaolin Li, Yajun Cui, Hongrui Liu, Tomoka Hasegawa, Minqi Li.

  Diabetic osteoporosis (DOP) is a metabolic bone disease characterized by skeletal fragility and impaired angiogenesis-osteogenesis coupling, in which type H vessel impairment has emerged as an important pathological feature. While adaptive immunity is known to regulate bone homeostasis, the immunometabolic mechanisms driving vascular dysfunction in DOP remain elusive. Here, we investigated whether pathological metabolic reprogramming of CD4+ T cells is linked to type H vessel impairment in DOP. CD4+ T cells from DOP mice exhibited enhanced glycolytic activation accompanied by increased hexokinase 2 (HK2) expression and elevated O-GlcNAcylation. In vitro, high glucose and palmitic acid (HGPA) treatment was associated with increased HK2 O-GlcNAcylation, HK2 stabilization, mitochondrial localization, and enhanced glycolytic activity in CD4+ T cells. These metabolic alterations were accompanied by senescence-associated and pro-inflammatory phenotypes, including upregulation of P53, P16, PD-1, IL-6, and IL-17 A, as well as enhanced T helper 17 (Th17) polarization. Co-culture experiments showed that HGPA-treated CD4+ T cells were associated with impaired endothelial viability, migration, tube formation, and reduced VEGFA/VEGFR2 expression. Pharmacological inhibition of O-GlcNAcylation or glycolysis partially attenuated CD4+ T cell dysfunction and improved endothelial angiogenic function. Collectively, these findings suggest that O-GlcNAcylation-associated HK2 glycolytic activation may contribute to CD4+ T cell dysfunction and type H vessel impairment in DOP. Targeting this immunometabolic pathway may represent a potential therapeutic strategy for diabetic skeletal complications.

Keywords:  Diabetic osteoporosis; Glycolysis; O-GlcNAcylation; T cell senescence; Th17; Type H vessels

DOI:  https://doi.org/10.1016/j.cellsig.2026.112694
Immunity. 2026 Jun 24. pii: S1074-7613(26)00231-1. [Epub ahead of print]

Stem-like precursors of exhausted Th cells upheld by a Tox-Myb-Eomes transcriptional hierarchy propagate Th cell responses in chronic infection.

Lifen Wen, Chun-Hsi Su, Nikita Potemkin, Lachlan Dryburgh, Lei Qin, Sining Li, Marcela De Lima Moreira, Ashraful Haque, Xiye Sun, Vincenzo Cinella, Jan Schroeder, Carlson Tsui, Axel Kallies.

  CD4+ T helper (Th) cells are critical drivers of adaptive immunity, but how their responses are maintained during chronic infection remains unclear. Here, we identified a population of CD4+ T cells that expressed CD62L and the inhibitory receptor PD-1 and exhibited both features of exhaustion and stemness. These cells acted as precursors of T helper (pTh) cells and sustained Th cell immunity during chronic lymphocytic choriomeningitis virus (LCMV) infection, giving rise to type 1 (Th1) and follicular T helper (Tfh) cells and cytotoxic-like T cells. pTh cells developed under conditions of high antigen exposure and depended on exhaustion and stemness-associated transcription factors TOX, EOMES, and MYB. Consequently, the maintenance of mature Th cells was severely compromised when CD4+ T cells lacked these factors. pTh cells also contributed to Th1 cell expansion upon PD-1 blockade. Overall, our findings reveal a molecular program and cellular hierarchy that preserve long-term CD4+ Th cell responses during chronic infection and immunotherapy.

Keywords:  CD4(+) T cells; LCMV; PD-1; checkpoint inhibition; exhaustion; lymphocytic choriomeningitis virus

DOI:  https://doi.org/10.1016/j.immuni.2026.06.001