bims-imseme 2026-01-25 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–01–25
thirty-one papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Cell cycle arrest enhances CD8+ T cell effector function by potentiating glucose metabolism and IL-2 signaling.
Medium-Chain Fatty Acid Receptor GPR84 Modulates Cytotoxic CD8 T cells Antitumor Immunity Through Metabolic Reprogramming.
Spatiotemporal regulation of energetic charge dictates T cell function.
Chronic stress drives liver cancer by impairing the hepatic kynurenine pathway and immune surveillance.
Aging Reshapes γ/δ T-Cell Immunity Through a Type I Interferon-Foxo1 Axis.
Basal level of ATF4 promotes T cell readiness for activation-induced proliferation.
Multiple myeloma derived sulfur dioxide drives CAR-T cell exhaustion by inducing mitochondrial dysfunction.
Nature Aging coming of age.
CD8+ T cell differentiation into NK-like effector cells drives transplant rejection.
NDUFS4, a mitochondrial complex I subunit, is essential for T-cell metabolic fitness and immune function.
Bispecific T cell engagers control solid tumors through clonal replacement and IL2-driven effector differentiation of CD8 T cells.
Unraveling CD8 lineage decisions reveals that functionally distinct CD8+ T cells are selected by different MHC-I thymic peptides.
Publisher Correction: SLC2A1+ tumour-associated macrophages spatially control CD8+ T cell function and drive resistance to immunotherapy in non-small-cell lung cancer.
Author Correction: Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells.
Single-Cell Profiling Across Immune Tissues and Organs Reveals Immunosenescence Signatures in Male Rhesus Monkeys.
How crosstalk at the immune synapse shapes T cell and dendritic cell biologys.
Serial Killing Assay Using Longitudinal Impedance-Based Tumor Cell Viability Measurement - A Useful Method to Assess T Cell Performance.
Meta-unstable mRNAs in activated CD8+ T cells are defined by interlinked AU-rich elements and m6A mRNA methylation.
Emerging frontiers in the mitochondrial regulation of dendritic cell biology.
Role of elevation of glycolysis in tumor-associated macrophages in glioblastoma immune evasion and therapeutic implications.
Functionally heterogeneous intratumoral CD4+CD8+ double-positive T cells can give rise to single-positive T cells.
The PI3Kδ inhibitor roginolisib (IOA-244) preserves T-cell function and activity.
Metabolic reprogramming in clear cell renal cell carcinoma: core pathways and targeted therapeutic strategies.
Targeting macrophage-derived SPP1 enhances CD8 T cell infiltration via ROS-DNA fragment/cGAS-STING/STAT1-mediated CXCL9/10 in tumor microenvironment.
Dextran-based T-cell expansion nanoparticles for manufacturing CAR T cells with augmented efficacy.
Cellular senescence as a therapeutic target for aging intervention.
Early-onset Palmijihwang-hwan treatment modulates phospholipid metabolism and gut microbiota for healthy aging: reducing adipose inflammation and oxidative stress.
SLC25A45: a gatekeeper for methylated amino acid metabolism.
Activation phenotypes defined by the coordinated expression of activation markers discriminate TCR-mediated and bystander T cell responses.
Inhibiting the Secreted RGDKGE Collagen Peptide Selectively Controls CD8+ T-Cell Migration on Denatured Collagen-IV and Enhances Their Accumulation in Tumors.
Fibroblastic reticular cells direct the initiation of T cell responses via CD44.

Nat Immunol. 2026 Jan 19.

Cell cycle arrest enhances CD8+ T cell effector function by potentiating glucose metabolism and IL-2 signaling.

Floortje J van Haften, Tetje C van der Sluis, Hanna S Hepp, Nils Mülling, Reza Nadafi, Bharath Sampadi, Suzanne van Duikeren, J Shirin Mostert, Rosemarijn van der Sterre, Peter A van Veelen, Graham A Heieis, Dominique M B Veerkamp, Thomas H Wesselink, Ward Vleeshouwers, Macha Beijnes, Iris N Pardieck, Eralin L F van Horssen, Anne F de Groot, Manon van der Ploeg, Judith R Kroep, Noel F C C de Miranda, Sabina Y van der Zanden, Jacques Neefjes, Hailiang Mei, Alfred C O Vertegaal, Bart Everts, Sjoerd H van der Burg, Ramon Arens.

Cell cycle-inhibiting chemotherapeutics are widely used in cancer treatment. Although the primary aim is to block tumor cell proliferation, their clinical efficacy also involves specific effector CD8+ T cells that undergo synchronized proliferation and differentiation. How CD8+ T cells are programmed when these processes are uncoupled, as occurs during cell cycle inhibition, is unclear. Here, we show that activated CD8+ T cells arrested in their cell cycle can still undergo effector differentiation. Cell cycle-arrested CD8+ T cells become metabolically reprogrammed into a highly energized state, enabling rapid and enhanced proliferation upon release from arrest. This metabolic imprinting is driven by increased nutrient uptake, storage and processing, leading to enhanced glycolysis in cell cycle-arrested cells. The nutrient sensible mTORC1 pathway, however, was not crucial. Instead, elevated interleukin-2 production during arrest activates STAT5 signaling, which supports expansion of the energized CD8+ T cells following arrest. Transient arrest in vivo enables superior CD8+ T cell-mediated tumor control across models of immune checkpoint blockade, adoptive cell transfer and therapeutic vaccination. Thus, transient uncoupling of CD8+ T cell differentiation from cell cycle progression programs a favorable metabolic state that supports the efficacy of effector T cell-mediated immunotherapies.

DOI: https://doi.org/10.1038/s41590-025-02407-0
Cancer Immunol Res. 2026 Jan 20.

Medium-Chain Fatty Acid Receptor GPR84 Modulates Cytotoxic CD8 T cells Antitumor Immunity Through Metabolic Reprogramming.

Phaethon Philbrook, Matthew J Dean, Maria Dulfary Sanchez-Pino, Li Qin Zheng, Jovanny Zabaleta, Julio A Vázquez-Martínez, Darwin Chang, Jessica K Mandula, Timothy I Shaw, Dorota Wyczechowska, Jone Garai, Ramesh Thylur Puttalingaiah, Amirsalar Mansouri, Weishan Huang, Satyajit Das, Shiun Chang, Jose R Conejo-Garcia, Paulo C Rodriguez, Augusto C Ochoa.

GPR84 is a medium-chain free fatty acid receptor predominantly expressed in myeloid cells. Previous studies have identified GPR84 as an enhancer of the pro-inflammatory myeloid cell responses and a regulator of metabolic homeostasis. However, the role of GPR84 in T cell function and metabolism remains largely unexplored. This study tested the effect of GPR84 modulation on CD8+ T cell function and metabolism in vitro and examined its effect on antitumor function in adoptive cellular therapy models. Pharmacological antagonism with GLPG1205 or genetic deletion of GPR84 promoted T cell differentiation, proliferation, cytokine production, and cytotoxicity, whereas agonism with DL175 reduced these functions. These functional changes were paralleled by changes in metabolic activity. Antagonism and genetic deletion increased glucose uptake, glycolysis, oxidative phosphorylation, and ATP production, which enhanced the overall cell energetic fitness, whereas agonism resulted in a quiescent energetic profile. Furthermore, antagonism or deletion of GPR84 in antigen-specific CD8+ T cells in adoptive cellular therapy models enhanced their antitumor effects in vivo. Thus, GPR84 inhibition improves CD8+ T cell function and may further enhance adoptive cellular therapies.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0695
Nat Commun. 2026 Jan 21. 17(1): 770

Spatiotemporal regulation of energetic charge dictates T cell function.

Aleksandra S Chikina, Béatrice Corre, Fabrice Lemaître, Philippe Bousso.

Immune cell functions are dictated by their differentiation state and regulated by transcriptional and epigenetic changes. Immune cell differentiation also controls the preferential metabolic pathways used for energy production. However, whether the energy charge of individual immune cells itself varies across time and space and regulates cell function remains to be fully understood. Here, we show that T cells harbor distinct energetic resources and function in different anatomical locations and times of the day. To monitor ATP: ADP ratio, an indicator of cellular energetic resources, we rely on SPICE-Met, a method that dissects energy metabolism in complex cell populations in vivo. We find that cells with the highest glycolytic capacity, including effector T cells and NK cells, exhibit the highest ATP: ADP ratio. Importantly, effector T cells but not naïve T cells display higher energetic charge when present in the blood compared to lymph nodes due to differential glucose availability. Energetic resources are also regulated in a circadian manner, being highest at the early rest phase. Importantly, differences in energetic charge are directly translated at the level of T cell function, impacting IFN-γ production. Thus, modulation of energetic charge and nutrient availability dictates immune cell function across time and space.

DOI: https://doi.org/10.1038/s41467-026-68559-1
Nat Metab. 2026 Jan 19.

Chronic stress drives liver cancer by impairing the hepatic kynurenine pathway and immune surveillance.

Renhui Sun, Deyan Jiao, Wenjing Yuan, Hao Wang, Lingtong Ren, Zhendong Fu, Jiaxuan Zhang, Xuetian Yue, Zhuanchang Wu, Chunyang Li, Huili Hu, Jianping Wang, Lifen Gao, Chunhong Ma, Xiaohong Liang.

Psychological stress is increasingly linked to liver disease, but the underlying mechanisms remain unclear. Here we show that chronic stress disrupts a brain-liver circuit that impairs hepatic CD8+ T cell immunity and accelerates liver cancer progression. Using both oncogene-driven and carcinogen-driven liver cancer models in male mice, we find that psychological stress disrupts catecholamine/β2-adrenergic receptor (ADRB2) signalling, which suppresses the expression of quinolinate phosphoribosyl transferase (QPRT), an enzyme of the kynurenine pathway, in hepatocytes. QPRT loss diverts kynurenine metabolism away from nicotinamide adenine dinucleotide (NAD+) synthesis towards kynurenic acid (KA) accumulation. This shift results in mitochondrial impairment and reduced effector function of liver CD8+ T cells. We confirm that ADRB2/QPRT expression correlates with hepatic NAD+ and KA levels and with CD8+ T cell frequency and function in human liver tissues. Importantly, ADRB2/QPRT overexpression in hepatocytes, or nicotinamide administration, recovers CD8+ T cell function in stressed mice and reduces liver cancer progression. These findings identify a stress-responsive metabolic checkpoint in the liver that links the nervous system to immune surveillance and may be therapeutically targeted in liver cancers.

DOI: https://doi.org/10.1038/s42255-025-01430-7
Aging Cell. 2026 Feb;25(2): e70389

Aging Reshapes γ/δ T-Cell Immunity Through a Type I Interferon-Foxo1 Axis.

Aurélie Durand, Sarah Porte, Eryang Xing, Christian Wu, Agnès Le Bon, Cédric Auffray, Bruno Lucas, Bruno Martin.

  Aging is associated with profound alterations in immune cell composition and function, yet the impact on peripheral γ/δ T-cell subsets remains incompletely understood. Here, we show that the peripheral γ/δ T-cell compartment is markedly remodeled with age in mice. Specifically, innate-like Ly-6C- CD44hi γ/δ T cells expand in secondary lymphoid organs (SLOs) of aged mice, while adaptive-like subsets decline. This age-related shift is accompanied by enhanced functionality, with Ly-6C- CD44hi γ/δ T cells from aged SLOs displaying increased IL-17 production both ex vivo and in vivo following LPS challenge. Mechanistically, this functional remodeling correlates with a significant decrease in the expression of the transcription factor Foxo1 in Ly-6C- CD44hi γ/δ T cells. Type I interferon signaling contributes to the age-dependent downregulation of Foxo1, as Ly-6C- CD44hi γ/δ T cells from aged mice lacking the IFN-α receptor maintain Foxo1 expression and exhibit reduced IL-17 production. Collectively, our findings reveal that aging, through type I interferon-driven modulation of Foxo1, promotes the expansion and enhanced pro-inflammatory activity of innate-like γ/δ T cells. These changes may reinforce immune surveillance in secondary lymphoid organs but could also contribute to age-associated immune dysregulation and inflammation.

Keywords:  Foxo1; aging; type I IFNs; γ/δ T cells

DOI:  https://doi.org/10.1111/acel.70389
iScience. 2026 Jan 16. 29(1): 114277

Basal level of ATF4 promotes T cell readiness for activation-induced proliferation.

Yushan Yi, Ce Luo, Jingyi Wang, Yujia Wang, Lixue Jin, Xiuyuan Sun, Jie Hao, Guoping Deng, Rong Jin, Qing Ge.

  Stress-response elements are required during late-phase T cell activation and differentiation. To investigate whether they are indispensable during the first 12-24 h post-stimulation when mitochondrial activation and metabolic reprogramming are critical, we activated Atf4-sufficient and Atf4-deficient T cells and tracked their earliest activation dynamics. We demonstrate that T cell activation-induced mTOR and GCN2 phosphorylation leads to the upregulation of ATF4 protein as early as 12 h after stimulation. This early induction of ATF4 has transcriptional activities that regulate stress response, signaling, and metabolism. Loss of Atf4 in T cells alters transcriptome dynamics, impairs amino acid transport and biosynthesis, and disrupts adaptive responses to ER stress and oxidative stress, resulting in defective effector cell differentiation in vitro or in vivo. Our findings suggest that a basal level of ATF4 during the early phase of T cell activation enhances the preparedness of cells to cope with integrated stresses during the activation course.

Keywords:  Cell biology; Immunology

DOI:  https://doi.org/10.1016/j.isci.2025.114277
Redox Biol. 2026 Jan 19. pii: S2213-2317(26)00038-8. [Epub ahead of print]90 104040

Multiple myeloma derived sulfur dioxide drives CAR-T cell exhaustion by inducing mitochondrial dysfunction.

Zhengyu Yu, Hua Lin, Jingran He, Linfeng Li, Zhongwang Wang, Kun Li, Ting Niu, Bingquan Qiu.

  Metabolic disorders mediated chimeric antigen receptor - T cell (CAR-T) exhaustion impaired cancer immunotherapy. Endogenous sulfur dioxide (SO2) derived from L-cysteine catalysis regulated immune cell functions. However, its role in CAR-T cell exhaustion remained unknown. In this study, we identified that SO2 accumulated in the bone marrow microenvironment of relapsed multiple myeloma patients inhibited CD8+ T cell and CAR-T cell infiltration and promoted a transcriptional profile consistent with functional exhaustion, leading to impaired antitumor immunity. Tumor cell derived SO2 altered mitochondrial morphology and disrupted mitochondrial membrane potential in CAR-T cells, accompanied by impaired cytokine secretion and loss of cytotoxic function. Mechanistically, SO2 enhanced interaction of dynamin-related protein 1 (DRP1) and voltage-dependent anion channel 1 and mitochondrial fission via DRP1 sulphenylation at cysteine 607 (Cys607), with abnormal increases in DRP1 GTPase activity, disrupting mitochondrial integrity. Site mutation of Cys607 in CAR-T cells abrogated DRP1 sulphenylation and restored mitochondrial structure and improves antitumor immunity. These findings define a novel redox-mediated mechanism of mitochondrial dysfunction in CAR-T cells exhaustion and identify the SO2-DRP1 axis as a potential therapeutic target to overcome metabolic exhaustion in CAR-T cell therapy.

Keywords:  CAR-T cell exhaustion; CAR-T therapy; DRP1; Mitochondrial dynamics; Multiple myeloma; Sulfur dioxide

DOI:  https://doi.org/10.1016/j.redox.2026.104040
Nat Aging. 2026 Jan;6(1): 1

Nature Aging coming of age.

DOI: https://doi.org/10.1038/s43587-025-01062-2
Mol Ther. 2026 Jan 21. pii: S1525-0016(26)00025-0. [Epub ahead of print]

CD8+ T cell differentiation into NK-like effector cells drives transplant rejection.

Dawei Zou, Stephanie G Yi, Yulin Dai, Luan Truong, Lillian W Gaber, Richard L Knight, Xiang Xiao, Rafik M Ghobrial, Xian C Li, Zhongming Zhao, Wenhao Chen, A Osama Gaber.

T cells are central drivers of transplant rejection, yet the differentiation fates underlying this process remain unclear. Using single-cell transcriptomic profiling of human kidney allograft biopsies, we identified a predominant infiltrating CD8+ T cell subset exhibiting killer cell lectin-like receptor (KLR)+ NK-like features. Mechanistic studies in mice showed that the KLR+ subset emerged de novo post-transplantation and dominated the CD8+ T cell infiltrate in rejecting allografts. These NK-like CD8+ T cells expressed high levels of interferon regulatory factor 4 (IRF4), and Irf4 deletion disrupted their differentiation and induced transplant acceptance. Therapeutically, either costimulation blockade or mTOR inhibition substantially reduced the generation of NK-like CD8+ T cells; however, the persistence of these cells ultimately led to rejection. Notably, combining costimulation blockade with mTOR inhibition completely abrogated their generation and enabled transplant acceptance. Together, these findings identify KLR+ NK-like CD8+ T cells as key mediators of transplant rejection, highlighting the need for more effective strategies to block their differentiation and improve transplant outcomes.

DOI: https://doi.org/10.1016/j.ymthe.2026.01.024
Front Immunol. 2025 ;16 1734203

NDUFS4, a mitochondrial complex I subunit, is essential for T-cell metabolic fitness and immune function.

Oded Shamriz, Zahala Bar-On, Omri Yosef, Leonor Cohen-Daniel, Ayelet Sheer, Or Reuven, Wajeeh Salaymeh, Amijai Saragovi, Raz Somech, Atar Lev, Hagar Mor-Shaked, Yuval Tal, Aviva Fattal-Valevski, Simon Edvardson, Michael Berger.

   Introduction: Mitochondrial metabolism is essential for T-cell function, but the roles of individual electron transport chain (ETC) components are unclear. Here, we aimed to explore the role of mitochondrial complex I (CI) subunit NADH:ubiquinone oxidoreductase iron-sulfur protein 4 (NDUFS4) in T-cell metabolic fitness and immunity.
Methods: We used a T cell-specific Ndufs4 knockout mouse model to find that NDUFS4 deficiency disrupts CI function, leading to metabolic and redox imbalances. Additionally, T cells from a patient with Leigh syndrome induced by NDUFS4 loss-of-function were analyzed.
Results: Ndufs4-deficient T cells exhibit impaired OXPHOS, reduced respiratory capacity, and increased glycolysis, accompanied by reactive oxygen species (ROS) accumulation and defective TCR-driven activation, including reduced proliferation and cytokine production. In vivo, Ndufs4(-/-) mice show T-cell lymphopenia and impaired humoral and cytotoxic immunity. Importantly, T cells from a single Leigh syndrome patient with an NDUFS4 loss-of-function variant showed similar defects, including impaired activation and proliferation.
Discussion: These findings highlight the importance of NDUFS4 for human immunity and establish a mechanistic link between complex I dysfunction and T-cell immunodeficiency. Our results identify NDUFS4 as a key regulator connecting mitochondrial integrity to adaptive immune function.

Keywords:  NDUFS4; NDUFS4 knockout mice; T cells; leigh syndrome (LS); mitochondria

DOI:  https://doi.org/10.3389/fimmu.2025.1734203
bioRxiv. 2025 Dec 06. pii: 2025.12.04.692214. [Epub ahead of print]

Bispecific T cell engagers control solid tumors through clonal replacement and IL2-driven effector differentiation of CD8 T cells.

Matthias Obenaus, Clara L Poupault, Christopher S McGinnis, Céline Prange, Hua Jiang, Leon L Su, Xiaojing Chen, Zhuang Miao, Joseph J Muldoon, Winnie Yao, Deepa Waghray, Qinli Sun, Justin Eyquem, Rogelio A Hernández-López, Ansuman T Satpathy, Julien Sage, K Christopher Garcia.

Bispecific T cell engagers (TCEs) often exhibit limited efficacy in solid tumors, in part due to immunosuppressive cues in the tumor microenvironment and low expression of targetable tumor antigens. Therapeutic strategies to improve TCE target sensitivity and enhance T cell effector functions therefore have significant translational potential. Here, we engineered TCEs that induce T cell activation in vitro against the low-abundance target antigens, TRP2/K b and DLL3. Despite in vitro activity in these models, TCE monotherapy showed limited control of tumor growth in immunocompetent mice. Leveraging this in vivo model of TCE treatment failure, we discovered that co-treatment with TCE and a CD25-biased Interleukin-2 (IL2) rescues anti-tumor activity. Further, multimodal single-cell transcriptomic and immune repertoire analyses revealed that TCE-IL2 combination therapy controlled tumors by recruiting and activating new CD8 + T cells into the tumor microenvironment. These findings demonstrate that TCE-mediated anti-tumor responses function through a CD8 + T cell clonal replacement mechanism that can be augmented by cytokine therapy.

DOI: https://doi.org/10.64898/2025.12.04.692214
Nat Immunol. 2026 Jan 19.

Unraveling CD8 lineage decisions reveals that functionally distinct CD8+ T cells are selected by different MHC-I thymic peptides.

Miho Shinzawa, Nicole Ramos, Khanh Bui, William Hajjar, Assiatu Crossman, Xiongfong Chen, Margaret Cam, Yousuke Takahama, Alfred Singer.

Thymocytes signaled by T cell antigen receptors to undergo positive selection acquire different functional fates while migrating through the thymus, but how this occurs remains uncertain. We now report that encoding CD8 co-receptors in both Cd4 and Cd8 gene loci modulates major histocompatibility complex (MHC-I) class I T cell antigen receptor signaling duration to generate all potential CD8+ T cell subsets. Strikingly, such mice revealed that functionally different CD8+ T cells are selected by different MHC-I thymic peptides. Thymocytes signaled by β5t-peptides produced by thymoproteasomes exclusively expressed in the thymic cortex invariably become cytotoxic CD8+ T cells indicating their signaling ceases when thymocytes leave the cortex; whereas thymocytes signaled by nonβ5t-peptides expressed throughout the thymus become either helper or innate memory CD8+ T cells because their signaling persists or recurs outside the cortex. Thus, it is because of their different thymic distributions that different MHC-I peptides select functionally different CD8+ T cells, integrating peptide specificity and CD8+ T cell function during positive selection and thymocyte migration.

DOI: https://doi.org/10.1038/s41590-025-02411-4
Nat Cell Biol. 2026 Jan 19.

Publisher Correction: SLC2A1+ tumour-associated macrophages spatially control CD8+ T cell function and drive resistance to immunotherapy in non-small-cell lung cancer.

Lei Wang, Han Chu, Degao Chen, Yuxuan Wei, Jia Jia, Liqi Li, Linfeng He, Lina Peng, Fangfang Liu, Shanshan Huang, Zheng Jin, Dong Zhou, WenFeng Fang, Tao Jiang, Shouxia Xu, Xiaofang Ding, Haoyang Cai, Xindong Liu, Qingzhu Jia, Bo Zhu, Qian Chu.

DOI: https://doi.org/10.1038/s41556-026-01874-3
Nat Immunol. 2026 Jan 20.

Author Correction: Autophagy repression by antigen and cytokines shapes mitochondrial, migration and effector machinery in CD8 T cells.

Linda V Sinclair, Tom Youdale, Laura Spinelli, Milica Gakovic, Alistair J Langlands, Shalini Pathak, Andrew J M Howden, Ian G Ganley, Doreen A Cantrell.

DOI: https://doi.org/10.1038/s41590-026-02433-6
Adv Sci (Weinh). 2026 Jan 20. e14353

Single-Cell Profiling Across Immune Tissues and Organs Reveals Immunosenescence Signatures in Male Rhesus Monkeys.

Shengnan Wang, Zhengna Zhu, Hongju Yang, Yaping Yan, Luyao Ran, Naixue Yang, Yichao Wang, Li Wu, Bing Bai, Weizhi Ji, Wei Si.

  Aging gradually impairs immune system function, yet its systemic features across immune organs remain poorly characterized in primates. Here, we perform single-cell transcriptomic profiling of bone marrow, spleen, mesenteric lymph nodes, and peripheral blood mononuclear cells from young and naturally aged male rhesus monkeys. Our study revealed extensive transcriptional remodeling across tissues, particularly the marked upregulation of GZMB expression across multiple cell types in aged monkeys, highlighting it as a candidate biomarker of immunosenescence. Gene regulatory network analysis identifies BHLHE40 as a key transcription factor enriched in multiple CD8+ T cell subtypes during aging, regulating pro-inflammatory and exhaustion-related genes. We also observe an age-associated expansion of CD8+ central memory T cells with increased CCL5 and reduced IL7R expression, consistent with a shift toward a dysfunctional state. In the bone marrow, we discover a distinct naïve B cell population with low PDCD4 expression that declines with age, potentially compromising humoral immunity. These findings offer a comprehensive single-cell atlas of immune aging in a non-human primate model, providing novel insights into cell-type-specific and tissue-dependent features of immunosenescence. Our work establishes a valuable resource for future translational studies and biomarker discovery in human aging.

Keywords:  immunosenescence; rhesus monkeys; single‐cell

DOI:  https://doi.org/10.1002/advs.202514353
Nat Rev Immunol. 2026 Jan 21.

How crosstalk at the immune synapse shapes T cell and dendritic cell biologys.

Noa B Martín-Cófreces, Diego Calzada-Fraile, Francisco Sánchez-Madrid.

In the context of adaptive immunity, T cells are activated by professional antigen-presenting cells (APCs) in a process that begins with peptide-MHC complexes on the APC being recognized by T cell receptor and CD3 co-receptor complexes on the T cell. This triggers a reorganization of T cell morphology, formation of an immune synapse, and the delivery of signals that ultimately culminate in nuclear activation. The interaction between T cells and APCs, such as dendritic cells (DCs), was originally viewed as a unidirectional information highway in which the APC instructs the T cell. It is now clear that bidirectional crosstalk occurs at the immune synapse and that T cells also shape APC functions. The concept of 'DC licensing' originally suggested an instructive role for T cells in modifying DC functions. More recent studies have provided important insight into the changes that occur in DCs during antigen-driven contacts with T cells at the immune synapse. In this Review, we discuss our current understanding of the bidirectional T cell-DC crosstalk that occurs at the IS and its relevance for immune responses and immunotherapies.

DOI: https://doi.org/10.1038/s41577-025-01262-2
J Vis Exp. 2025 Dec 30.

Serial Killing Assay Using Longitudinal Impedance-Based Tumor Cell Viability Measurement - A Useful Method to Assess T Cell Performance.

Tengis Tschaidse, Marcel P Trefny, Emanuele Carlini, David Andreu-Sanz, Stefanos Michaelides, Ngoc Thien Thu Nguyen, Sebastian Kobold.

Chimeric antigen receptor (CAR) cell therapy has revolutionized the treatment of specific hematologic malignancies. However, a significant portion of patients experience relapse because of antigen loss, antigen downregulation, or T cell exhaustion. These challenges highlight the need for functional assays that can evaluate the killing capacity and persistence of CAR T cells under chronic antigen stimulation. Serial killing assays, which measure the ability of CAR T cells to repeatedly eliminate tumor targets, offer valuable insights into the durability and potency of CAR T cell responses. Here, we present an impedance-based assay using the Real-Time Cell Analysis (RTCA) system to quantify CAR T cell-mediated serial killing in vitro. Tumor cells are repeatedly seeded and allowed to adhere to assay-specific E-plates before the addition of CAR T cells at defined effector-to-target (E:T) ratios. The platform continuously monitors tumor cell viability without labels, capturing dynamic cytotoxicity with high temporal resolution. Core readouts include Cell Index (CI) kinetics, tumor-cell killing rate, and time-to-target clearance. The progressive decline in killing capacity observed upon repeated tumor-target engagements serves as a marker of acquired CAR T cell dysfunction, often termed T cell exhaustion. Together, these metrics allow precise evaluation of CAR T cell function at various E:T ratios and enable direct comparison among different CAR T cell constructs or co-treatments over time. To enhance cost efficiency, we developed a plate-washing procedure that enables the reuse of assay E-plates without compromising assay performance or data integrity. The optimized workflow reduces assay cost while preserving analytical robustness. This approach enables affordable and scalable preclinical assessment of CAR T cell function, facilitating improvements in cell-therapy design.

DOI: https://doi.org/10.3791/69623
Nat Commun. 2026 Jan 22. 17(1): 160

Meta-unstable mRNAs in activated CD8+ T cells are defined by interlinked AU-rich elements and m6A mRNA methylation.

Paulo A Gameiro, Iosifina P Foskolou, Yumna A Butt, Aniek A M Martens, Klara Kuret Hodnik, Igor Ruiz de Los Mozos, Nordin D Zandhuis, Žan Hozjan, Veronica M Kot, Rupert Faraway, Michiel Vermeulen, Monika C Wolkers, Randall S Johnson, Jernej Ule.

CD8+ T cells can rapidly produce effector molecules following activation. This activation triggers rapid changes in gene expression that rely on the control of mRNA levels via multiple mechanisms, including RNA modifications. N6-methyladenosine (m6A) is an abundant post-transcriptional modification that promotes the decay of messenger RNAs in the cytosol. However, how recognition of m6A sites is integrated with other regulatory mechanisms that alter the fate of immunoregulatory mRNAs in CD8+ T cells remains unexplored. Here, we apply the m6A-iCLIP and GLORI methods to identify the importance of m6A sites flanked by AU-rich elements (AREs) within the 3'UTRs of CD8+ T cell mRNAs. Presence of such ARE-flanking m6A motifs predicts meta-unstable mRNAs that rapidly decay upon CD8+ T cell activation. We demonstrate interdependent effects of mutations in the identified AREs and RRACHs on TNF mRNA stability. The ARE-flanking m6A sites in these mRNAs show particularly high iCLIP crosslinking of YTHDF proteins, which are also identified by proteomic interactome analyses along with additional novel RNA-binding proteins. Our study reveals a crosstalk between m6A and ARE-dependent mechanisms in CD8+ T cells, providing new approaches for modulating mRNA decay in T cell activation.

DOI: https://doi.org/10.1038/s41467-025-67762-w
Redox Biol. 2026 Jan 14. pii: S2213-2317(26)00030-3. [Epub ahead of print]90 104032

Emerging frontiers in the mitochondrial regulation of dendritic cell biology.

B Chen, J U Mayer.

  Dendritic Cells are central players of our immune system, linking innate sensing to adaptive immunity through antigen presentation and T cell priming. Beyond transcriptional and cytokine-based regulation, mitochondria are emerging as potential regulators of Dendritic Cell biology. While still in its infancy, evidence is accumulating that mitochondrial pathways affect Dendritic Cell differentiation; that mitochondrial remodeling and bioenergetic rewiring underpin Dendritic Cell maturation and activation in response to pathogenic and inflammatory stimuli and that shifts in mitochondrial and redox dynamics, reactive oxygen species production and mitochondrial DNA release coincide with Dendritic Cell activation and co-stimulatory molecule expression. Mitochondria are furthermore involved in regulating Dendritic Cell migration by influencing cellular metabolism and cytoskeletal dynamics and support the antigen processing and presentation machinery, thereby dictating the quality of the initiated T cell response. Importantly, mitochondrial checkpoints also regulate Dendritic Cell survival, balancing immune activation with timely cell death to preserve immune homeostasis. While the exact pathways of mitochondrial regulation are just beginning to be understood, disruptions in these programs can be far reaching. During aging, progressive mitochondrial dysfunction has been associated with impaired Dendritic Cell differentiation, diminished antigen presentation and impaired T cell responses. Similar defects have been observed in chronic diseases and cancer, leading us to hypothesize that genetic disorders linked to mitochondrial dysfunction also lead to defects in Dendritic Cell biology, impacting clinical symptoms such as immune dysregulation, heightened infection risk and inappropriate chronic inflammation. Therefore, in this review we have summarized the emerging roles of mitochondrial regulation in Dendritic Cell biology and discuss therapeutic opportunities to restore immune competence by targeting mitochondrial and redox pathways in settings of Dendritic Cell dysfunction. These insights aim to encourage further research into these topics and propose targeted metabolic reprogramming as a new therapeutic strategy for healthy ageing and chronic disease management.

Keywords:  Dendritic cell; Mitochondria; Mitochondrial diseases; Mitochondrial dynamics; Redox biology

DOI:  https://doi.org/10.1016/j.redox.2026.104032
PNAS Nexus. 2026 Jan;5(1): pgaf396

Role of elevation of glycolysis in tumor-associated macrophages in glioblastoma immune evasion and therapeutic implications.

Jiezhong Chen, Lin Zhu, Tom Lawson, Christopher G Proud, Liming Dai.

Glioblastoma is a highly aggressive brain cancer with significant mortality, primarily due to CD8+ T cell deficiency, which obstructs effective treatment outcomes. The dysfunction and exhaustion of CD8+ T cells are strongly linked to tumor-associated macrophages (TAMs), which, when exhibiting heightened glycolysis, secrete interleukin-10 and express programmed death ligand 1, both of which suppress CD8+ T cell function. This is under the control of cytokines and growth factors in the glioblastoma tumor microenvironment which activate multiple signaling pathways in TAMs. Moreover, TAMs can increase the aggressiveness of cancer cells by enhancing the activation of oncogenic signaling pathways. Understanding the mechanisms of the roles of glycolysis in TAM development and function as well as the regulation of glycolysis by various signaling pathways has substantial therapeutic implications. In this review, we summarize the most recent progress in TAMs, focusing on glycolysis and examine their interactions with both CD8+ T cells and cancer cells, and their control by signaling pathways. We also discuss in detail the potential therapeutic strategies prompted by new discoveries regarding glycolysis and signaling pathways in TAMs.

DOI: https://doi.org/10.1093/pnasnexus/pgaf396
Proc Natl Acad Sci U S A. 2026 Jan 27. 123(4): e2506168123

Functionally heterogeneous intratumoral CD4+CD8+ double-positive T cells can give rise to single-positive T cells.

Tony Li, Arielle Ilano, Marcel Arias-Badia, Diamond Luong, Hewitt Chang, Serena S Kwek, Kathryn Allaire, Arun Chumber, Mason Sakamoto, Matthew Clark, Averey Lea, Mark Bridge, Brandon Chen, Eric Liu, Sima Porten, Maxwell V Meng, Lauren I R Erlich, David Y Oh, Lawrence Fong.

  Conventional single-positive (SP) CD4+ and CD8+ T cells recognize tumor antigens and help mediate clinical responses with cancer immunotherapy. Double-positive CD4+CD8+ (DP) T cells have also been described in human cancers, but their role in the tumor microenvironment remains unclear. By generating a multiomic single cell atlas of DP and SP T cells, we find that DP T cells possess phenotypic heterogeneity similar to SP T cells that includes multiple clonally expanded populations of cytotoxic DP T cells in human renal cell carcinoma (RCC). These intratumoral DP T cells can mediate both MHC class I- and class II-dependent killing of autologous tumor cells. In addition, transcriptional profiling of DP TCR-bearing T cells revealed a gene signature enriched for clinical responders to PD-1 blockade in advanced RCC. We confirm prior observations of SP T cells transitioning into DP T cells and more notably, demonstrate that intratumoral T cells are capable of bidirectional differentiation in which DP T cells serve as precursors to SP T cell sin vivo. In the latter scenario, intratumoral DP T cells are shown to express Rag2, suggesting that the tumor may act as an extrathymic site of T cell development. These findings reveal the multiple roles that DP T cells can possess in antitumor immunity.

Keywords:  T cells; immunotherapy; tumor immunity

DOI:  https://doi.org/10.1073/pnas.2506168123
Mol Oncol. 2026 Jan 22.

The PI3Kδ inhibitor roginolisib (IOA-244) preserves T-cell function and activity.

Elise Solli, Alessio Bevilacqua, Mathias Wenes, Denis Migliorini, Lars van der Veen, Sigrid S Skånland, Giusy Di Conza, Kjetil Taskén.

  PI3K inhibitors (PI3Ki) have shown promise in some hematological cancers, but further development has been hampered by reports of serious immune-related adverse effects. Thus, identification of effective PI3Ki lacking these adverse effects is desirable. Here, we evaluated the in vitro effects of the investigational PI3Ki roginolisib (IOA-244) and the approved PI3Ki idelalisib on immune cells and leukemic cells. Roginolisib inhibited chronic lymphocytic leukemia cell signaling and viability in a manner comparable to idelalisib. Both drugs specifically inhibited PI3K-signaling in T cells, validating their on-target effects. Both idelalisib and roginolisib reduced regulatory T-cell frequency in a concentration-dependent manner, with idelalisib demonstrating greater potency. Both inhibitors also reduced T-cell activation and proliferation, but to differing extents. However, only idelalisib induced a pronounced impairment of CD8+ T-cell cytotoxic function. Furthermore, idelalisib treatment promoted differentiation of conventional CD4+ T cells into Th1, Th2, and Th17 subsets-a response not observed with roginolisib. In summary, roginolisib functions as an effective PI3K inhibitor on leukemic cells while preserving T-cell functions, posing it as an alternative to current PI3K inhibitors.

Keywords:  CD4+ T helper cell; CD8+ cytotoxicity; PI3K inhibitor; T‐cell function; chronic lymphocytic leukemia; regulatory T cells

DOI:  https://doi.org/10.1002/1878-0261.70203
Front Genet. 2025 ;16 1752384

Metabolic reprogramming in clear cell renal cell carcinoma: core pathways and targeted therapeutic strategies.

MingWei Zhan, BinBin Zhao, Haote Chen, Junjie Wu, Run Shi, Feng Gao, Lin Zhao, Jingyu Zhu.

  Clear cell renal cell carcinoma (ccRCC), rooted in VHL loss and dysregulated HIF signaling, is defined by a sweeping metabolic overhaul: intensified glycolysis, a "downshifted" TCA cycle, the buildup of lipid droplets and cholesteryl esters, and a pronounced dependence on glutamine and one-carbon metabolism-all tightly intertwined with an immunosuppressive microenvironment. Drawing on single-cell and spatial multi-omics, metabolomic and lipidomic profiling, and imaging-based evidence, this article maps the critical nodes of carbon, lipid, amino-acid, and one-carbon pathways, and their crosstalk with ferroptosis. It highlights how metabolic heterogeneity-exemplified by the DCCD spectrum-shapes prognosis and therapeutic response. The review further synthesizes how metabolic-immune coupling, including lipid metabolic rewiring in TAMs and MDSCs, and lactate/lipid stress in CD8+ T cells, contributes to immune-therapy resistance. On the translational front, HIF-2α inhibitors (such as belzutifan), strategies that suppress or oxidize lipids to trigger ferroptosis, and interventions targeting glutamine and one-carbon metabolism show promise when rationally combined with ICIs, TKIs, or anti-angiogenic therapies. We propose a stratified decision framework anchored in DCCD state, lipid-droplet/PLIN2 phenotype, ferroptosis sensitivity, and HIF activity, and discuss the emerging roles of radiopathomics (e.g., CT HU-PLIN2 coupling) and circulating metabolic fingerprints in companion diagnostics. Looking toward clinical deployment, advancing standardization within MSI/IBSI and FAIR data principles-and launching biomarker-enriched, prospective multicenter trials-will be essential to demonstrate the real-world value of precision metabolic oncology in the personalized treatment of ccRCC.

Keywords:  DCCD; belzutifan; clear cell renal cell carcinoma (ccRCC); ferroptosis; glutamine metabolism; immunometabolism; lipid droplets/PLIN2; one-carbon metabolism

DOI:  https://doi.org/10.3389/fgene.2025.1752384
J Immunother Cancer. 2026 Jan 22. pii: e013697. [Epub ahead of print]14(1):

Targeting macrophage-derived SPP1 enhances CD8 T cell infiltration via ROS-DNA fragment/cGAS-STING/STAT1-mediated CXCL9/10 in tumor microenvironment.

Juanjuan Wang, Yi Shi, Yunhuan Gao, Ningning Zhu, Yuqing Liu, Yuan Zhang, Chen Xu, Rongcun Yang.

   BACKGROUND: Elevated levels of SPP1+ tumor-associated macrophages (TAMs) are associated with reduced CD8+ T cell infiltration and poorer prognosis in cancer patients, but direct evidence demonstrating a causal role for SPP1+ TAMs in excluding CD8+ T cells is still missing. The precise mechanisms by which SPP1-activated signaling pathways and macrophage-derived factors regulate CD8+ T cell trafficking remain poorly understood.
METHODS: We established multiple tumor mouse models to study the function of macrophage SPP1 in the tumor environment, especially its role in the relationship between macrophages and CD8 T cells. We combined the single-cell (sc) RNA sequencing data of clinical tumor samples and tumor tissues from Spp1fl/fl-Lyz2-Cre mice to identify the differences in SPP1-related genes and found that SPP1 could regulate the expression of CXCL9 and CXCL10 in macrophages. Through Western blotting, immunofluorescence staining, and flow cytometry analyses, we elucidated the mechanistic basis by which macrophage-specific SPP1 deficiency suppressed tumorigenesis.
RESULTS: This study demonstrated that macrophage-derived SPP1 played a crucial role in suppressing CD8 T cell infiltration, promoting tumor progression, and diminishing the effectiveness of immune checkpoint inhibitor (ICI) therapy. Sc-RNA sequencing analysis revealed a marked increase in CD8 T cell populations within tumor tissues of Spp1fl/fl-Lyz2-Cre mice. Furthermore, a negative correlation was observed between CD8 T cells and SPP1 macrophages in human colorectal cancer specimens. Genetic deletion of SPP1 in macrophages markedly enhanced tumor growth suppression in a manner dependent on CD8 T cell-mediated immunity. Mechanistically, SPP1 deficiency in macrophages led to elevated mitochondrial reactive oxygen species (ROS) production, resulting in the accumulation of cytosolic double-stranded DNA (dsDNA) fragments. This accumulated dsDNA activated the cGAS-STING pathway, leading to subsequent STAT1 phosphorylation. The enhanced STAT1 activity upregulated the expression of chemokines CXCL9 and CXCL10, thereby facilitating CD8 T cell recruitment into the tumor microenvironment.
CONCLUSIONS: Deletion of SPP1 in TAMs upregulates CXCL9/10 production by activating the ROS-DNA fragment/cGAS-STING/STAT1 pathway, thereby enhancing CD8 T cell infiltration, inhibiting tumor progression, and improving ICI treatment outcomes in tumors.

Keywords:  Immunotherapy; Intratumoral; JAK-STAT; Macrophage; T cell

DOI:  https://doi.org/10.1136/jitc-2025-013697
Nat Commun. 2026 Jan 20.

Dextran-based T-cell expansion nanoparticles for manufacturing CAR T cells with augmented efficacy.

Tao Zheng, Keerthana Ramanathan, Maria Ormhøj, Mikkel Rasmus Hansen, Hólmfridur Rósa Halldórsdóttir, Hanxi Li, Kamilla Kjærgaard Munk, Carlos Rodriguez-Pardo, Rasmus Ulslev Wegener Friis, Islam Seder, Peter M H Heegaard, Klaus Qvortrup, Hinrich Abken, Yi Sun, Sine Reker Hadrup.

Adoptive T cell therapy using chimeric antigen receptor (CAR) engineered T cells is currently being explored in multiple cancer types beyond leukemia/lymphoma. A key step in CAR-T cell manufacturing is the activation and expansion of T cells, which facilitates viral transduction, however, may hamper T cell fitness and reduce in vivo persistence. "T-Expand" is developed for T cell activation and expansion, comprising dextran-based nanoparticles conjugated with anti-CD3 and anti-CD28 antibodies. The nanoparticles trigger robust polyclonal expansion of human T cells with efficiency in the range of commercial microbeads (Dynabeads™). Engineered in the presence of T-Expand, CD19 CAR T cells display enhanced proliferative capacity, cytotoxicity and persistence in vitro, and furthermore, exhibit potent anti-lymphoma activity in mouse models, resulting in complete tumor clearance at one fourth of the CAR T cell dose. Importantly, T-Expand is biocompatible with no observed toxicity, circumventing removal steps after T cell expansion compared to DynabeadsTM. As a biocompatible T cell expansion platform, T-Expand simplifies the manufacturing process while enhancing T cell persistence and functionality, and thereby holds promise for increasing clinical efficacy of CAR T cell therapy.

DOI: https://doi.org/10.1038/s41467-025-67868-1
Biomed J. 2026 Jan 17. pii: S2319-4170(26)00004-1. [Epub ahead of print] 100948

Cellular senescence as a therapeutic target for aging intervention.

Youkun Bi, Guangju Ji.

  Cellular senescence is a stress-induced cellular state that contributes to tissue dysfunction, chronic inflammation, and a broad range of aging-associated pathologies. The accumulation of senescent cells (SnCs) disrupt normal tissue function, positioning them as drivers of pathological decline and therapeutic targets for aging intervention. Accordingly, multiple senescence-targeted strategies have been developed, including senolytics, senomorphics, senescence immunotherapy, and restoration-oriented interventions. These approaches aim to mitigate senescence-driven pathology by eliminating senescent cells, modulating their secretory activity, or restoring cellular function. Ongoing advancements will require precise stratification of senescent states, careful assessment of long-term safety, and the integration of optimized delivery systems for targeted therapeutic outcomes.

Keywords:  Cellular senescence; Restoration-oriented interventions; Senescence immunotherapy; Senolytics; Senomorphics

DOI:  https://doi.org/10.1016/j.bj.2026.100948
NPJ Aging. 2026 Jan 20.

Early-onset Palmijihwang-hwan treatment modulates phospholipid metabolism and gut microbiota for healthy aging: reducing adipose inflammation and oxidative stress.

So Min Lee, Jung Joo Yoon, Hye Yoom Kim, Sarah Shin, You Mee Ahn, Dong Seok Cha, Ho-Sub Lee, Jeeyoun Jung.

Aging is characterized by progressive physiological decline and increased vulnerability to metabolic and inflammatory disturbances. Palmijihwang-hwan (PM), a traditional East Asian herbal formula, has been used empirically for age-related complaints, but its mechanistic basis remains unclear. Here, we evaluated the effects of early-onset PM administration (starting at 2 months of age) on longevity-related phenotypes and metabolic regulation. PM significantly prolonged lifespan in Caenorhabditis elegans and improved survival in ICR mice without evident toxicity. Preventive PM administration reduced epididymal white adipose tissue (eWAT) mass and circulating insulin/adipokine levels. Lipidomic analysis showed a shift from lysophospholipids toward phospholipids, accompanied by downregulation of PLA2G7, indicating attenuation of adipose inflammation. PM also reshaped the gut microbiota, decreasing inflammation-associated taxa such as Oscillibacter valericigenes, and lowered adipose IL-6 and TNF-α expression. Collectively, these findings indicate that preventive early-onset PM administration modulates the gut microbial composition, counteracting the age-related enrichment of inflammation-related bacteria.

DOI: https://doi.org/10.1038/s41514-026-00334-4
Trends Endocrinol Metab. 2026 Jan 22. pii: S1043-2760(25)00283-8. [Epub ahead of print]

SLC25A45: a gatekeeper for methylated amino acid metabolism.

Yue Zhang, Yan Tian, Xianghui Fu.

  The metabolite substrates of numerous transporters remain largely elusive. Two recent studies by Khan et al. and Dias et al. identify SLC25A45 as a mitochondrial transporter of methylated amino acids that supports de novo carnitine synthesis, providing a valuable strategy for deorphanizing transporters and novel insights into cytoplasm-mitochondria communication and metabolic coordination.

Keywords:  carnitine biosynthesis; fasting; machine learning; mitochondria; trimethyllysine

DOI:  https://doi.org/10.1016/j.tem.2025.12.005
iScience. 2026 Feb 20. 29(2): 114551

Activation phenotypes defined by the coordinated expression of activation markers discriminate TCR-mediated and bystander T cell responses.

Tamara J C Schenk, Martijn Vos, Yannick van Sleen, Debbie van Baarle, Teun Guichelaar.

  Studying activation of antigen-specific T cells is essential for understanding adaptive immune response to pathogens, tumors, and vaccines. Flow cytometry is commonly used to identify antigen-specific T cells based on the induction of activation-induced markers (AIMs). However, these markers are also expressed on bystander T cells activated by cytokines produced by antigen-activated T cells. This complicates the distinction between true T cell receptor (TCR)-activated- and bystander T cells. We developed an approach to differentiate between these types of cells. We stimulated human PBMCs with anti-CD3 antibody (TCR-mediated) or supernatant of activated T cells, IL-2, or IL-15 (bystander activation). We analyzed AIM co-expression patterns on CD4+ and CD8+ T cells, and defined activation phenotypes that distinguish TCR-activated from bystander-activated T cells. In anti-viral responses, peptide stimulation mainly induced bystander activation, yet bystander T cells contributed minimally to cytokine production. Our findings provide a framework for identifying T cell response types in diverse clinical contexts.

Keywords:  Immune response; Immunological methods

DOI:  https://doi.org/10.1016/j.isci.2025.114551
Am J Pathol. 2026 Feb;pii: S0002-9440(25)00365-7. [Epub ahead of print]196(2): 598-617

Inhibiting the Secreted RGDKGE Collagen Peptide Selectively Controls CD8+ T-Cell Migration on Denatured Collagen-IV and Enhances Their Accumulation in Tumors.

XiangHua Han, Jennifer M Caron, Peter C Brooks.

The ability of the immune system to control malignant tumors depends in part on the migratory ability of CD8+ T cells. Developing in-depth cellular and molecular understanding into how changes in the structural organization of collagen-IV differentially governs site-specific CD8+ T-cell migration through restrictive tissue barriers is challenging given the dynamic biomechanical alterations occurring in the basement membranes of tumor blood vessels. Thus, uncovering new mechanisms regulating CD8+ T-cell migration through structurally altered or denatured collagen-IV may allow the development of clinically useful strategies to selectively enhance immune cell infiltration of tumors in a context-dependent manner. This work provides evidence that a secreted RGDKGE-containing collagen peptide limits CD8+ T-cell migration on denatured forms of collagen-IV, but not on normal triple helical collagen-IV by a unique mechanism. This novel pathway involves the context-dependent regulation of myosin IXB (MYO9B) and Yes-associated protein-1 (YAP) in CD8+ T cells, ultimately leading to altered F-actin polarization and selectively reduced migration on denatured collagen-IV that is enriched in basement membranes of tumor vessels. In addition to defining a previously unknown mechanism that contributes to the site-specific control of CD8+ T-cell migration, these studies provide a strategy to selectively reverse the inhibitory effects of this endogenously secreted collagen peptide using a function-blocking antibody, resulting in enhanced accumulation of CD8+ T cells in tumors growing in vivo.

DOI: https://doi.org/10.1016/j.ajpath.2025.09.008
Nature. 2026 Jan 21.

Fibroblastic reticular cells direct the initiation of T cell responses via CD44.

Xavier Y X Sng, Valentina Voigt, Iona S Schuster, Peter Fleming, Felix A Deuss, Mohammed H Abuwarwar, Serani L H van Dommelen, Georgia E G Neate, Riley M Arnold, Harry L Horsnell, Sheridan Daly, Bagher Golzarroshan, Antiopi Varelias, Stewart D Lyman, Anthony A Scalzo, Geoffrey R Hill, Scott N Mueller, Matthew E Wikstrom, Richard Berry, Jamie Rossjohn, Anne L Fletcher, Christopher E Andoniou, Mariapia A Degli-Esposti.

The movement of dendritic cells and T cells within secondary lymphoid organs is critical for the development of adaptive immune responses1,2. Central to this process is the fibroblastic reticular cell (FRC) network, which forms a highly organized conduit system that facilitates the movement of and interactions between dendritic cells and T cells3-6. Previous studies have partly characterized how FRCs support these interactions7,8. However, the molecular mechanisms that operate under physiological conditions remain unknown. Here we show that the viral protein m11, encoded by the herpesvirus murine cytomegalovirus (CMV), inhibits antiviral immunity by targeting the FRC network and interfering with a critical function of cellular CD44. We found that m11 binds to CD44 and established that m11 perturbs the molecular interactions of CD44 with its natural ligand, hyaluronic acid. The interaction of m11 with CD44 impairs the trafficking of dendritic cells within the spleen, thereby impeding efficient priming of naive T cells and the initiation of antiviral CD8 T cell responses. The targeting of CD44 by CMV reveals CD44 as a molecule that is essential to the functioning of the FRC network and uncovers a previously unrecognized stroma-based mechanism that is critical for the generation of effective T cell responses.

DOI: https://doi.org/10.1038/s41586-025-09988-8