bims-imseme 2026-03-01 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–03–01
23 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

DADA Enhances CD8+ T Cell Stemness to Improve Anti-Tumor Immunity and Immunotherapy Efficacy.
[Mitochondria in Cancer and Immunity].
Law-NQO1 redox boosts the pentose phosphate pathway to confer stem-like properties and antitumor durability in effector CD8+ T cells.
Bacteria-Derived Nanobody-Decorated Nanoplatform Restores T Cell Immunity Post-Radiotherapy.
Immunosenescence in Human Disease: Mechanistic Insights and Therapeutic Opportunities.
Identification of a Highly Functional Effector CD8+ T Cell Program after Transplantation in Mice and Humans.
Oncolytic Zika virus therapy leverages CCR2+ monocytes to boost anti-glioblastoma T cell responses.
Piezo1 as a mechanical checkpoint in T cell immunotherapy for solid tumors.
TOX drives CD4+ TH1 effector function, antitumor immunity and autoimmune pathology.
RUNX phosphorylation specifies CD8+ T cell lineage during positive selection.
PD-1 protects expanding human T cells from premature restimulation-induced cell death by modulating TCR and CD28 signaling.
Memory-like CD8+ T cells lacking PD-1 adapt to persistent stimulation by reducing TCR signal transduction rather than increasing exhaustion.
Metabolic quiescence of naive-like memory T cells precedes and maintains antigen-specific T cell memory.
Temporal Dissection of TGF-β signaling reveals differential impact during female reproductive mucosal CD8 resident memory T cell differentiation.
HDAC1 modulates sepsis-induced immunosuppression by driving the exhaustion of CD8+ T cells.
Fungal-derived cellobiose metabolic pathway fuels T cells to bypass intratumoral glucose competition.
Single-cell transcriptomics reveal intrinsic and systemic T cell aging in COVID-19 and HIV.
Glutathione is critical for NK cell-mediated immunity.
Integrated chronic in vivo and in vitro screens uncover NFIL3 as a driver of T cell dysfunction.
Dual PD-1/IL-2Rα targeting restores CD8+ T cell fitness via STAT5/CD47 axis in SMARCA4-deficient NSCLC.
Epigenetic editing to advance CAR T cell therapy.
IFN-driven lipid synthesis shutdown in CD4⁺ T cells during acute SIV infection and persistent OXPHOS with ART initiation.
T Cell Receptor Co-Stimulation Through Magnetogenetic Tools: A Platform for Wireless Rewiring of Cellular Signaling.

Adv Sci (Weinh). 2026 Feb 27. e19765

DADA Enhances CD8+ T Cell Stemness to Improve Anti-Tumor Immunity and Immunotherapy Efficacy.

Mingyue Bi, Fei Li, Heng Jiang, Lingling Gu, Mengjie Sun, Kunyu Lu, Pianpian Liu, Ruyue Xie, Wenqiang Ma, Meijuan Zheng, Xianwei Wang, Xuefu Wang, Jingjing Cong.

  Progenitor exhausted CD8+ T (Tpex) cells have recently been identified as a stem-like T cell subset that mediates durable anti-tumor immune responses and represents a pivotal population responsive to immunotherapies. Here, it is demonstrated that diisopropylamine dichloroacetate (DADA) facilitates CD8+ T cell-mediated anti-tumor immunity and promotes Tpex cells accumulation in the tumor microenvironment. Mechanistically, DADA promotes the conversion from pyruvate to Acetyl-CoA by inhibiting pyruvate dehydrogenase kinase. This process leads to increased oxidative phosphorylation (OXPHOS) and mitochondrial fitness, thereby enhancing CD8+ T cells stemness. Treatment of mice with DADA improves the efficacy of PD-1 blockade. Furthermore, the in vitro expansion of chimeric antigen receptor (CAR)-T cells supplemented with DADA confers them with stemness characteristics, contributing to improved anti-tumor efficacy. Collectively, this study illustrates how DADA-mediated metabolic reprogramming in CD8+ T cell enhances their stemness, underscoring its potential for anti-tumor therapy.

Keywords:  CD8+ T cell; anti‐tumor immunity; metabolic reprogramming; stemness

DOI:  https://doi.org/10.1002/advs.202519765
Gan To Kagaku Ryoho. 2026 Feb;53(2): 73-79

[Mitochondria in Cancer and Immunity].

Takahiro Taki, Teruya Morinaga, Yosuke Togashi.

Mitochondria are multifunctional organelles responsible not only for ATP production via oxidative phosphorylation but also for a wide range of cellular activities, including biosynthesis, redox regulation, signal transduction, and the control of apoptosis. In both cancer and immune cells, mitochondrial function plays various roles that extend beyond mere energy production. While cancer cells are known for the Warburg effect‒an enhanced glycolysis even in the presence of oxygen-they also actively utilize mitochondrial metabolism to fuel tumor progression. Furthermore, mutations in mitochondrial DNA(mtDNA) and alterations in nuclear genes encoding mitochondrial proteins contribute to tumorigenesis through various mechanisms, such as epigenetic modifications and the evasion of apoptosis. In immune cells, such as T cells and macrophages, mitochondrial metabolism is crucial for their differentiation and functional regulation. Key processes such as T cell activation, memory formation, and exhaustion, as well as macrophage functional polarization and inflammatory responses, are tightly linked to mitochondrial functional states. Recently, intercellular mitochondrial transfer within the tumor microenvironment has emerged as a significant phenomenon. Cancer cells can acquire mitochondria from surrounding cells to enhance their metabolic capacity and therapeutic resistance. Conversely, the transfer of mitochondria from cancer cells to T cells has been shown to suppress antitumor immune responses through metabolic dysfunction and homoplasmic replacement of T cell mtDNA. Based on these findings, therapeutic strategies targeting mitochondria are under investigation. These include inhibiting mitochondrial metabolism in cancer cells, boosting mitochondrial metabolism in T cells, and blocking intercellular mitochondrial transfer. Although preclinical studies have yielded promising results, further research is necessary to establish effective clinical therapies that can precisely modulate the complex metabolic interplay between cancer and immune cells.
Cell Chem Biol. 2026 Feb 25. pii: S2451-9456(26)00033-4. [Epub ahead of print]

Law-NQO1 redox boosts the pentose phosphate pathway to confer stem-like properties and antitumor durability in effector CD8+ T cells.

Jianfeng Pang, Zengge Wang, Cuixia Yang, Lin Huang, Yiran Qiu, Hui Wang, Keling Huang, Xiaoxue Li, Zifeng Yang, Hudan Pan, Liang Liu, Xuemei Tong, Bin Li, Mingjun Zhang, Lin Zhong, Zhigang Li, Feng Wang.

  Metabolic reprogramming is pivotal for modulating antitumor immunity of T cell. Here, we identify a distinct CD8+ T cell state, designated as pentose phosphate pathway (PPP)-enhanced effector T cell (Tpeec), which is induced by NQO1-mediated redox cycling. We demonstrate that lawsone (Law) serves as a specific NQO1 substrate. The Law-NQO1 axis elevates mitochondrial ROS through NADPH consumption, activating the AKT-FOXO1 signaling cascade to drive effector differentiation. Importantly, this redox-dependent process amplifies PPP activity, redistributing glucose flux to not only enhance mitochondrial fitness but also promote ribose-5-phosphate (R5P) accumulation, endowing Tpeecs with superior proliferative capacity and stemness. Consequently, Tpeecs exhibit robust antitumor efficacy, as validated both in vitro and in vivo. Our findings uncover a critical metabolic axis linking redox cycling to PPP-driven stemness in CD8+ T cells, thereby reconciling their effector function with long-term persistence. This discovery positions NQO1-bioactivatable agents as promising therapeutic tools for optimizing T cell immunotherapy.

Keywords:  CD8(+) T cell; NQO1; antitumor immunity; glucose metabolism; lawsone; metabolic reprogramming; mitochondrial ROS; pentose phosphate pathway

DOI:  https://doi.org/10.1016/j.chembiol.2026.02.001
ACS Nano. 2026 Feb 26.

Bacteria-Derived Nanobody-Decorated Nanoplatform Restores T Cell Immunity Post-Radiotherapy.

Jinzhou Cai, Xiangming Han, Yu Zhang, Rui Qian, Siqi Ma, Zetong Chen, Yujie Zhang, Pei Pei, Kai Yang.

  T cell exhaustion within the tumor immune microenvironment (TIME) impairs the efficacy of radioimmunotherapy. Here, we demonstrate that X-ray radiotherapy induces arginine metabolic dysregulation and PD-L1 upregulation in the tumor microenvironment (TME), suppressing T cell metabolism and driving the expansion of PD-1+TIM-3+ exhausted T cells, thereby promoting immunosuppression. To address this, we design a biomimetic hybrid immunomodulator (arg/Bnb-L) by engineering BL-21 bacterial membranes to display PD-L1 nanobodies and fusing them with l-arginine-loaded liposomes. This nanoplatform simultaneously blocks PD-1/PD-L1 immune checkpoint signaling and restores T cell metabolic activity while promoting dendritic cell maturation. In murine tumor models, arg/Bnb-L combined with radiotherapy significantly enhances CD8+ T cell infiltration, reduces exhausted T cell populations, maintains cytotoxic T lymphocyte function, and inhibits tumor progression and metastasis. Our study elucidates a dual mechanism underlying radiotherapy-induced immunosuppression and offers a promising strategy to enhance radioimmunotherapy outcomes through targeted metabolic and immunologic reprogramming.

Keywords:  PD-L1 nanobody; T cell exhaustion; T cell metabolism; TIME; radiotherapy

DOI:  https://doi.org/10.1021/acsnano.6c00839
Biomol Ther (Seoul). 2026 Mar 01. 34(2): 238-248

Immunosenescence in Human Disease: Mechanistic Insights and Therapeutic Opportunities.

Young-In Kim, Seo-Hee Oh, Tae Kyoung Lim, Heewon Lee, Sebin Lee, Sun-Young Chang.

  Immunosenescence, an age-associated decline in immune function, is increasingly recognized as a central determinant of health and disease in older adults. Characterized by thymic involution, loss of naïve T cells, contraction of T cell receptor diversity, accumulation of senescent and exhausted lymphocytes, and a chronic inflammatory state known as inflammaging, immunosenescence compromises both innate and adaptive immune responses. Immunosenescence contributes to the pathogenesis of diverse age-related diseases. In autoimmune and metabolic diseases, premature accumulation of senescent T cells and impaired regulatory T cell function drive chronic inflammation and tissue damage, while in neurodegenerative diseases, microglial aging and sustained neuroinflammation exacerbate neuronal loss. These findings highlight immunosenescence as a unifying mechanism linking aging to systemic and organ-specific pathologies. Advances in biomarker discovery, including phenotypic markers, telomere attrition, and epigenetic signatures, have enabled the quantitative assessment of immune aging, while emerging therapeutic strategies, such as cytokine modulation, mTOR inhibition, senolytics, and epigenetic reprogramming, show promise in restoring immune competence. Here, we summarize recent research on immunosenescence in various diseases, particularly chronic inflammatory, metabolic, and neurodegenerative diseases, and suggest novel strategies for the development of senolytic drugs.

Keywords:  Chronic inflammatory disease; Immunosenescence; Inflammaging; Metabolic disease; Neurodegenerative disease; Senolytics

DOI:  https://doi.org/10.4062/biomolther.2025.222
Am J Transplant. 2026 Feb 21. pii: S1600-6135(26)00103-6. [Epub ahead of print]

Identification of a Highly Functional Effector CD8+ T Cell Program after Transplantation in Mice and Humans.

Riley P Leathem, Joel S Freibaum, Gregory S Cohen, Robin Welsh, Yukai Tang, Marina W Shirkey, Sanniddhya B Bardhan, Ryo Hatano, Chikao Morimoto, Byoung Chol Oh, Daniela Čiháková, Jonathan S Bromberg, Scott M Krummey.

  To better understand the mechanism by which T cells mediate allograft rejection, we investigated the fate and function of graft-specific CD8+ T cells expressing the activated isoform of CD43 in mice and humans. Agonism of the CD43 1B11 receptor in vitro induced CD8+ T cell proliferation in the presence of sub-threshold antigen stimulation, and CD43 1B11 agonism in vivo overcame costimulation-blockade induced tolerance and enhanced CD8+ T cell cytokine production and cytotoxic function. Effector CD43 1B11+ CD8+ T cells expressed high levels of T-bet, but also maintained IL-7Rα, and TCF-1 expression at both effector and memory timepoints. In adoptive transfer experiments, CD43 1B11+ CD8+ T cells were persistent following graft rechallenge and also formed TCF-1+IL-7Rα+ memory cells. Human CD8+ T cells expressing CD43 and the glycosyltransferase GCNT1 were present in rejecting kidney allografts and had high expression of IFNG, ICOS, and perforins/granzymes. In healthy human donors and transplant candidates, the CD43 1D4 mAb clone defined antigen-experienced cytokine-producing CD8+ T cells. In sum, these data support an important role for activated CD43+ CD8+ T cells as potent effectors, and point to a potential role for CD43 1B11 signaling in augmenting effector functions in the context of sub-threshold antigen or costimulation.

Keywords:  alloimmunity; costimulation blockade; effector CD8(+) T cells; tolerance

DOI:  https://doi.org/10.1016/j.ajt.2026.02.020
Neuro Oncol. 2026 Feb 23. pii: noag037. [Epub ahead of print]

Oncolytic Zika virus therapy leverages CCR2+ monocytes to boost anti-glioblastoma T cell responses.

Kevin S Cashman, Akshitkumar M Mistry, Ashwani Kesarwani, Amanda De Andrade Costa, Jonah Daneshmand, Hammad Ur Rehman, Matthias Mack, Michael S Diamond, Milan G Chheda, Sharmila Nair.

   BACKGROUND: Glioblastoma (GBM) is a lethal brain tumor with limited treatment options, largely due to profound immune suppression within the tumor microenvironment (TME), the failure of current immunotherapies to restore CD8+ T cell function, and persistence of glioma stem cells (GSCs) after treatment. Oncolytic Zika virus (ZIKV) is a promising therapeutic that selectively targets GSCs and remodels the TME to enhance anti-tumor CD8+ T cell responses. In this study we investigated how ZIKV efficacy in GBM is driven through monocytes.
METHODS: We performed single-cell RNA sequencing and T cell receptor (TCR) sequencing to evaluate CD8+ T cell responses following ZIKV treatment. We used CellChat to define signaling networks between ZIKV-activated CCR2+ monocytes and CD8+ T cells in the TME. We used syngeneic, immunocompetent murine GBM models to validate mechanisms in vivo, applying genetic and antibody-based approaches to impair CCR2+ monocyte trafficking and function.
RESULTS: ZIKV induced clonal expansion of tumor-infiltrating CD8+ T cells enriched in granzyme B and perforin-1, with reduced expression of exhaustion markers. CCR2+ monocytes were essential for the recruitment, proliferation, and effector functions of anti-tumor CD8+ T cells in the TME. Disruption of monocyte trafficking or function impaired these responses, diminishing cytotoxic activity and T cell recruitment.
CONCLUSIONS: ZIKV-driven activation and recruitment of CCR2+ monocytes supports robust anti-tumor CD8+ T cell responses by enhancing cytotoxicity and limiting exhaustion. These findings highlight the previously unappreciated therapeutic potential of modulating monocyte-T cell crosstalk to overcome immune suppression in GBM.

Keywords:  CCR2+ monocytes; CD8+ T cells; Zika virus; glioblastoma; myeloid

DOI:  https://doi.org/10.1093/neuonc/noag037
Front Pharmacol. 2026 ;17 1722027

Piezo1 as a mechanical checkpoint in T cell immunotherapy for solid tumors.

Xinmu Cui, Jianan Zhao, Huajie Tian.

  T cell-based immunotherapies exhibit limited efficacy against solid tumors, a challenge primarily attributed to the immunosuppressive and mechanically hostile tumor microenvironment (TME). Within this context, the mechanosensitive ion channel Piezo1 has emerged as a key TME mechanosensor, yet its role in modulating T cell-mediated anti-tumor immunity remains to be fully elucidated. This review aims to synthesize existing evidence on Piezo1's regulation of T cell functions, including activation, proliferation, and infiltration, and its broader impact on immunotherapy for solid tumors. We highlight Piezo1's dual regulatory function in the immune landscape: acute activation robustly enhances T cell effector functions and cytotoxicity, whereas chronic stimulation within the stiff TME paradoxically promotes T cell exhaustion. Importantly, preclinical studies demonstrate that modulating Piezo1 signaling, particularly in combination with matrix normalization synergistically enhances the infiltration, persistence, and overall antitumor efficacy of adoptive T cells and endogenous immune responses. These findings position Piezo1 as a promising mechanical checkpoint for improving T cell therapies. Nevertheless, significant challenges persist for clinical implementation, including the heterogeneity of mechanical signals and the pleiotropic nature of Piezo1 across different cell types. Future research should therefore focus on developing T cell-specific mechanotherapies, identifying novel targets, and validating mechanical biomarkers to guide patient stratification, thereby accelerating the clinical translation of "mechanoimmunology".

Keywords:  Piezo1; T cell exhaustion; T cells; chimeric antigen receptor (CAR)-T cells; mechanoimmunology; solid tumors; tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fphar.2026.1722027
Nat Immunol. 2026 Feb 27.

TOX drives CD4+ TH1 effector function, antitumor immunity and autoimmune pathology.

Brianna Naizir, Andrew C Scott, Paul Zumbo, Simon Grassmann, Joe N Frost, Joseph C Sun, Doron Betel, Andrea Schietinger.

TOX is a nuclear factor critical for thymic development of CD4+ thymocytes, natural killer and innate lymphoid cells. In post-thymic antigen-specific CD8+ T cells, TOX is highly expressed in settings of chronic antigen encounter such as cancer and chronic infection and required for the persistence of exhausted CD8+ T cells. The role of TOX in CD4+ T cells is less clear. Here, we show that TOX is critical for CD4+ type 1 helper T (TH1) cell differentiation. Gain-of-function and loss-of-function studies show that TOX induces TH1 cell-associated molecular programs that drive TH1 cell-like phenotypes and interferon-γ production. TOX expression in CD4+ T cells from individuals with cancer was associated with increased cytotoxicity, antitumor immunity and improved responses to immunotherapy, as well as pathogenic responses in autoimmune and inflammatory diseases in mice and humans. Thus, TOX has opposing functions in CD4+ versus CD8+ T cells: while TOX is associated with CD8+ T cell exhaustion and generally with poor responsiveness to immunotherapy, in CD4+ T cells TOX drives TH1 cell fate commitment and is associated with antitumor immunity and pathogenic autoimmune responses.

DOI: https://doi.org/10.1038/s41590-026-02453-2
Nat Immunol. 2026 Feb 27.

RUNX phosphorylation specifies CD8+ T cell lineage during positive selection.

DOI: https://doi.org/10.1038/s41590-026-02455-0
Cell Death Dis. 2026 Feb 26.

PD-1 protects expanding human T cells from premature restimulation-induced cell death by modulating TCR and CD28 signaling.

Katherine P Lee, Sara Elster, Benjamin Epstein, Camille M Lake, Andrew L Snow.

Programmed cell death-1 (PD-1) is a co-inhibitory receptor expressed on T cells that dampens TCR and CD28 signaling in the immunological synapse. PD-1 is significantly upregulated on T cells in the tumor microenvironment, where it promotes exhaustion in the context of chronic antigen restimulation. Exhaustion renders T cells hyporesponsive and ineffectual, but potentially resistant to restimulation-induced cell death (RICD). Restimulation-induced cell death (RICD) is a critical propriocidal apoptosis program triggered in activated T cells upon robust TCR re-engagement, which serves to constrain effector T cell expansion and longevity to prevent collateral tissue damage. While the checkpoint function of PD-1 has profound implications for cancer immunotherapy, the role of PD-1 in regulating newly activated T cells remains unclear. We hypothesized that PD-1 attenuates RICD sensitivity in human effector T cells by modulating TCR signal strength. Here we show that transient upregulation of PD-1 helps to protect clonally expanding human CD4+ and CD8 + T cells from premature RICD, with only moderate protection noted in terminally-differentiated, PD-1lo effector CD8 + T cells. Restimulation of T cells with beads containing PD-L1 results in significant apoptosis resistance, dependent on PD-L1 dosage and the proximity of PD-L1 to the TCR and CD28. Interestingly, PD-L1 demonstrated a more significant RICD rescue with CD28 co-ligation as opposed to TCR engagement alone, suggesting PD-1 signaling targets both signaling pathways in this context. Furthermore, biochemical/proteomic data suggest PD-1 modulates proximal signaling downstream of both TCR and CD28 and influences the expression of specific pro/anti-apoptotic proteins that govern RICD sensitivity. Despite the original assumption of PD-1 as a programmed death-inducing protein, our research reveals that homeostatic expression of PD-1 in clonally expanding T cells confers RICD resistance that promotes T cell survival and persistence. These findings present significant implications for understanding how blocking or engaging the PD-L1:PD-1 signaling axis may influence apoptosis sensitivity in both normal and exhausted T cells to alter adaptive immune responses.

DOI: https://doi.org/10.1038/s41419-026-08530-6
Front Immunol. 2026 ;17 1743170

Memory-like CD8+ T cells lacking PD-1 adapt to persistent stimulation by reducing TCR signal transduction rather than increasing exhaustion.

Mélanie Charmoy, Julia M Maier, Tania Wyss, Vijaykumar Chennupati, Catherine Sabatel, Laurie Bonneaux, Alexandre Dumez, Romain Veber, Greta Guarda, Werner Held.

  CD8+ T cells respond to persistent stimulation during chronic viral infection by stably expressing co-inhibitory receptors and other exhaustion-related molecules. Here we addressed how memory-like CD8+ T (TML) cells, which sustain the immune response to chronic infection thanks to their stem-like properties, adapt to chronic stimulation when they cannot express the co-inhibitory receptor PD-1. We found an increased initial generation and stable long-term persistence of TML cells lacking PD-1 during chronic viral infection. However, these cells had a reduced ability regenerate upon acute restimulation in the context of a recall response. Mechanistically, the lack of PD-1-mediated inhibition was not compensated by an increased expression of other co-inhibitory receptors or exhaustion related molecules. Rather, the absence of PD-1 resulted in a reduced capacity of the TCR to activate TML cells and to express stemness genes including Myb and Klf4. Similar albeit weaker effects on TML cells were noted when PD-1 engagement was transiently interrupted due to anti-PD-L1 treatment. Thus, stem-like CD8+ T cells responding to chronic viral infection adapt to the absence of PD-1-dependent co-inhibitory signals by further reducing TCR-mediated activation signaling, likely to prevent excessive or prolonged stimulation of these cells.

Keywords:  CD8 T cells; chronic viral infection; exhaustion; lymphocytic choriomeningitis virus (LCMV); stemness

DOI:  https://doi.org/10.3389/fimmu.2026.1743170
Nat Immunol. 2026 Feb 24.

Metabolic quiescence of naive-like memory T cells precedes and maintains antigen-specific T cell memory.

Sina Frischholz, Ev-Marie Schuster, Myriam Grotz, Christine Schülein, Julia Benz, Katharina Kocher, Lucia Klotz, Szilard Varga, Theresa Hiltner, Rayya Alsalameh, Jan Esse, Johannes Träger, Jürgen Held, Frederik Graw, Jürgen Pahle, Bernd Spriewald, Luca Gattinoni, Veit R Buchholz, Felix Drost, Benjamin Schubert, Simon Rothenfußer, Dirk H Busch, Christian Bogdan, Kilian Schober.

Metabolic activity shapes cell fate but remains challenging to capture in vivo with high resolution. Here we performed longitudinal metabolic and phenotypic profiling of human antigen-specific CD8+ T cells after yellow fever vaccination using flow cytometry and single-cell RNA sequencing. As assessed by protein translation rates, CD8+ T cells upregulated glycolysis to fuel anabolic needs for proliferation but predominantly used oxidative phosphorylation for energy production during the acute phase (days 7-28) after vaccination. Simultaneously, CD8+CD62L+CD45RA- central memory T cells were the most metabolically active subset, whereas CD8+CD62L-CD45RA+ effector T cells underwent metabolic shutdown. Weakly differentiated CD8+CD62L+CD45RA+CD95- naive-like memory T cells showed minimal activity, relied solely on oxidative phosphorylation and were preferentially maintained 26 years postvaccination, reinforcing the link between cellular quiescence and longevity. Our study highlights quiescence as a key feature for long-term immunological memory formation in humans.

DOI: https://doi.org/10.1038/s41590-026-02421-w
Mucosal Immunol. 2026 Feb 19. pii: S1933-0219(26)00022-X. [Epub ahead of print]

Temporal Dissection of TGF-β signaling reveals differential impact during female reproductive mucosal CD8 resident memory T cell differentiation.

Mohammad H Hasan, Ying Lin, Joselynn Wallace, Farha J Mithila, Jessica Pacia, Geongoo Han, Khanhlinh Dinh, Chaoyu Ma, Nu Zhang, Lalit K Beura.

  Resident memory CD8 T cell (TRM) development progresses through distinct stages beginning with activation of naive T cells into effectors in lymphoid organs, trafficking of effectors to target tissue via blood, and final TRM differentiation at the tissue of residence under the influence of the local microenvironment. The cytokine TGF-β has emerged as a central regulator of TRM formation, but how TGF-β modulates these distinct stages of TRM differentiation is not known. Combining an epithelial organoid system and genetic mouse models that limit TGF-β availability or restrict CD8 T cell-specific TGF-β signaling, here we probed the temporal requirement of TGF-β in the female reproductive tract (FRT) TRM formation. We found that restricting total or active TGF-β accessibility during naive T cell stage didn't perturb CD8 T cells' differentiation into TRM. However, abrogation of TGF-β signaling either during effector differentiation or early memory formation significantly reduced epithelial TRM differentiation. Even mature CD103+ CD8 TRM cells relied on TGF-β signaling for their continued persistence. Memory CD8 T cells generated in the absence of TGF-β signaling exhibit reduced proliferation after antigenic recall. Taken together, these suggest a stage-specific role of TGF-β in antiviral FRT mucosal TRM formation with implications for improving vaccination approaches.

Keywords:  CD8 resident memory T cells; Female reproductive tract; Memory T cell differentiation; TGF-β

DOI:  https://doi.org/10.1016/j.mucimm.2026.02.005
JCI Insight. 2026 Feb 23. pii: e197224. [Epub ahead of print]11(4):

HDAC1 modulates sepsis-induced immunosuppression by driving the exhaustion of CD8+ T cells.

Liu Di, Jiang-Bo Fan, Rui Wang, You Li, Wan-da Bi, Si-Yuan Huang, Heng-Hai Nie, Xi-Feng Feng, Hua-Cai Zhang, Juan Du, Xiao-Fei Huang, An-Yong Yu, Zhe Xu, Fei Xia, Jian-Xin Jiang, Shuang-Shuang Dai, Xiang Xu, Zhen Wang, Ling Zeng.

  Sepsis, a systemic inflammatory response to infection, remains a leading cause of mortality in intensive care units, with sepsis-induced immunosuppression being a critical pathophysiological process. In this study, we investigated the role of histone deacetylase 1 (HDAC1) in sepsis-induced CD8+ T cell exhaustion, a key driver of immunosuppression. Clinical analyses of patients with sepsis revealed that reduced peripheral blood lymphocyte levels, particularly CD8+ T cell depletion, strongly correlated with worsened outcomes. In a murine sepsis model, single-cell RNA-Seq revealed a significant decrease in the proportion of CD8+ T cells and an increase in the proportion of exhausted CD8+ T cells in mouse lungs. Adoptive transfer of CD8+ T cells effectively reduced sepsis mortality by preserving organ function. We further demonstrated that HDAC1 expression was significantly upregulated in CD8+ T cells from patients with sepsis. In vitro studies showed that HDAC1 inhibition preserved CD8+ T cell function by maintaining T cell activity and reducing the expression of inhibitory molecules such as PD-1. Pharmacological inhibition of HDAC1 reduced mortality and reversed CD8+ T cell exhaustion by restoring the balance between activator protein-1 (AP-1) and nuclear factor of activated T cells (NFAT). Additionally, we found that HDAC1 directly interacted with NFAT1, promoting its nuclear translocation and further enhancing the expression of inhibitory molecules. Our findings highlight HDAC1 as a potential therapeutic target for sepsis-induced immunosuppression. By elucidating the molecular mechanisms underlying HDAC1-mediated immunosuppression, we have provided potential strategies for developing immunomodulatory therapies for the treatment of sepsis.

Keywords:  Adaptive immunity; Immunology; Infectious disease; Inflammation

DOI:  https://doi.org/10.1172/jci.insight.197224
Cell. 2026 Feb 24. pii: S0092-8674(26)00102-9. [Epub ahead of print]

Fungal-derived cellobiose metabolic pathway fuels T cells to bypass intratumoral glucose competition.

Matthew L Miller, Timothy J Thauland, Smriti Sameer Nagarajan, Wenqi Ellen Zuo, Miguel A Moreno Lastre, Manish J Butte.

  Solid tumors harbor immunosuppressive microenvironments that inhibit tumor-infiltrating lymphocytes (TILs) through the voracious consumption of glucose. We sought to restore TIL function by providing them with an exclusive fuel source. The glucose disaccharide cellobiose, which is the building block of cellulose, contains a β-1,4-glycosidic bond that animals (or their tumors) cannot hydrolyze, but fungi and microbes have evolved enzymes to catabolize cellobiose into useful glucose. We equipped mouse T cells and human chimeric antigen receptor (CAR)-T cells with two proteins derived from fungi that enable import and hydrolysis of cellobiose, and we demonstrated that cellobiose supplementation during glucose withdrawal restores key anti-tumor T-cell functions: viability, proliferation, cytokine production, and cytotoxic killing. Engineered T cells offered cellobiose suppress tumor growth and prolong survival. Offering exclusive access to a natural disaccharide augments cancer immunotherapies. This approach could be used to answer questions about glucose metabolism across many cell types, biological processes, and diseases.

Keywords:  CAR-T cell; T cells; cellobiose; glucose; immunotherapy; metabolism; tumors

DOI:  https://doi.org/10.1016/j.cell.2026.01.015
Aging (Albany NY). 2026 Feb 08. 18(1): 5-29

Single-cell transcriptomics reveal intrinsic and systemic T cell aging in COVID-19 and HIV.

Alan Tomusiak, Sierra Lore, Morten Scheibye-Knudsen, Eric Verdin.

  Biomarkers of aging offer insights into how diseases and interventions affect biological systems. However, most current biomarkers are based on bulk cell measurements, making it difficult to distinguish between changes driven by shifts in cell type composition (systemic effects) versus intrinsic changes within individual cells. To address this, we used single-cell RNA sequencing to analyze aging-related changes at both the cellular and bulk levels. We developed Tictock (T immune cell transcriptomic clock), a single-cell transcriptomic clock capable of predicting age and cell type across six human T cell subsets. Applying Tictock, we found that acute COVID-19 is associated with increased proportions of CD8+ cytotoxic T cells, whereas T cell composition remains stable in people with HIV on antiretroviral therapy (HIV+ART). Both COVID-19 and HIV+ART are linked to an increase in transcriptomic age, specifically within naïve CD8+ T cells. Gene Ontology enrichment of 209 genes shared across six clock models identified common pathways including the cytosolic small ribosomal subunit, TNF receptor binding, and cytosolic ribosome components. A correlation was also observed between aging and mean transcript length. These findings underscore the promise of single-cell transcriptomic biomarkers to disentangle the systemic and cell-intrinsic components of immune aging and to measure immune aging.

Keywords:  aging; aging biomarkers; intrinsic aging; systemic aging; transcriptomic clock

DOI:  https://doi.org/10.18632/aging.206353
Cell Rep. 2026 Feb 23. pii: S2211-1247(26)00064-1. [Epub ahead of print]45(3): 116986

Glutathione is critical for NK cell-mediated immunity.

Luana Guerra, Melanie Grusdat, Takumi Kobayashi, Joseph Longworth, Henry Kurniawan, Davide G Franchina, Georgios Theodorakis, Carole Binsfeld, Charlène Verschueren, Lynn Bonetti, Anouk Ewen, Leticia Soriano-Baguet, Sarah Alhamouieh, Sophie Farinelle, Catherine Dostert, Ying Chen, Vasilis Vasiliou, Eric Vivier, Philipp A Lang, Dirk Brenner.

  Natural killer (NK) cells are essential for immune protection against tumors and viruses. Disease environments impose oxidative stress and impair immune cell functions. Glutathione (GSH) is a major cellular antioxidant and is critical for the immune response, but how it modulates NK cell function remains largely unknown. Using a mouse model with a specific deletion of the catalytic subunit of glutamate-cysteine ligase (Gclc) in NK cells, we demonstrate that GSH supports interleukin-15 (IL-15)-driven activation of NK cells. Gclc deficiency causes an intracellular accumulation of reactive oxygen species (ROS), which impairs the metabolism of NK cells. This is accompanied by defective proliferation and cytokine production concurrent with subverted mTOR and STAT5 activation. During acute lymphocytic choriomeningitis virus (LCMV) infection, Gclc-deficient NK cells are unable to suppress the antiviral T cell response. Remarkably, Gclc deficiency impairs NK cell-mediated protection against tumor lung metastases. Our findings highlight an essential role of GSH in maintaining NK cell functionality.

Keywords:  CP: immunology; CP: metabolism; IL-15; LCMV; NK cells; cancer; cytotoxic T cells; glutathione; immunometabolism; mTOR; metastasis; redox metabolism

DOI:  https://doi.org/10.1016/j.celrep.2026.116986
Cancer Discov. 2026 Feb 27.

Integrated chronic in vivo and in vitro screens uncover NFIL3 as a driver of T cell dysfunction.

Nayan Jain, Yuzhe Shi, Celina May, Sneha Mitra, Philip Bucher, Anton Dobrin, Zeguo Zhao, Sophie Hanina, Vinagolu K Rajasekhar, Yonghong Yao, Jorge Mansilla-Soto, Josef Leibold, Christina S Leslie, Francisco J Sanchez-Rivera, Judith Feucht, Michel Sadelain.

CAR therapy has transformed the treatment landscape for hematological malignancies but its efficacy in solid tumors is limited, owing in part to insufficient functional persistence of the engineered T cells. To elucidate the basis for their functional decline, we conducted integrated chronic in vivo and in vitro screens of 400 transcription factors, which revealed NFIL3 as a driver of CAR T cell dysfunction. Genetic disruption of NFIL3 in CAR T cells sustains their expansion, increases cytokine production, overall restraining terminal differentiation. Loss of NFIL3 enhances CAR T cell efficacy, improving tumor control and prolonging survival in xenograft and syngeneic mouse tumor models across different CAR designs. Under chronic stimulation, disruption of NFIL3 establishes a transcriptional state predictive of favorable clinical outcomes. Our findings underscore the power of comprehensive in vivo genetic screens integrated with multi-parameter in vitro assessment and identify NFIL3 as a novel therapeutic target to enhance cancer immunotherapy.

DOI: https://doi.org/10.1158/2159-8290.CD-25-1524
Cell Rep Med. 2026 Feb 20. pii: S2666-3791(26)00050-9. [Epub ahead of print] 102633

Dual PD-1/IL-2Rα targeting restores CD8+ T cell fitness via STAT5/CD47 axis in SMARCA4-deficient NSCLC.

Xiaoling Shang, Bo Cheng, Zhenxiang Li, Haoyu Wang, Chenyue Zhang, Ning Tang, Liwen Wang, Chenglong Zhao, Jiamao Lin, Haiyong Wang.

  SMARCA4-deficient non-small cell lung cancer (NSCLC) is a genomically distinct and clinically aggressive subtype characterized by primary resistance to immune checkpoint inhibitors. This study identifies that SMARCA4 deficiency profoundly disrupts the interleukin (IL)-2-STAT5 signaling pathway in tumor-infiltrating CD8+ T cells by suppressing IL-2 receptor alpha (IL-2Rα) (CD25) expression, leading to severe T cell exhaustion and resistance to PD-1 inhibition. An engineered PD-1/IL-2 bispecific antibody (bsAb) with α-receptor-targeting activity reverses this defect across multiple preclinical models by co-engaging PD-1 and delivering a CD25-targeted IL-2 signal, thereby restoring STAT5 activation and effector function in exhausted CD8+ T cells. Mechanistically, PD-1/IL-2 bsAb-driven STAT5 activation transcriptionally upregulates CD47 on CD8+ T cells, which shields them from macrophage-mediated phagocytosis and enhances T cell survival in the tumor microenvironment. These findings delineate a role for the IL-2-STAT5-CD47 axis in immune evasion and suggest reactivating this pathway with PD-1/IL-2 bsAb may represent a therapeutic strategy to overcome resistance in this subtype.

Keywords:  CD47; IL-2; NSCLC; SMARCA deficiency; immunotherapy

DOI:  https://doi.org/10.1016/j.xcrm.2026.102633
Clin Epigenetics. 2026 Feb 23.

Epigenetic editing to advance CAR T cell therapy.

Laura Horvathova, Marianne G Rots, Valerie R Wiersma.

  Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer treatment by enabling the selective targeting and elimination of tumor cells. Although CAR T therapy offers a potential cure for haematological cancers, 40-60% of patients do not reach a durable response. In solid tumors, limited infiltration and the immunosuppressive tumor microenvironment have so far hindered clinical translation. Central to these challenges are T cell-intrinsic programs, including differentiation into short-lived effector cells and progressive exhaustion. Epigenetic modifications regulate T cell activation, memory formation, and exhaustion, thereby critically shaping CAR T cell persistence and therapeutic efficacy. Early studies have demonstrated that disrupting or inhibiting key epigenetic regulators such as ten-eleven translocation 2 (TET2) or DNA methyltransferase 3A (DNMT3A) can bias CAR T cells toward memory-like, non-exhausted states with superior antitumor activity. Building on these findings, gene-targeted epigenetic editing has recently emerged as a next-generation approach, offering precise, durable, and reversible reprogramming of gene expression without introducing DNA breaks. Proof-of-concept studies have demonstrated targeted and durable silencing of key inhibitory receptors such as programmed cell death protein 1 (PD-1) and lymphocyte activation gene 3 (LAG-3) as a safe strategy to shape CAR T cell phenotypes. Beyond phenotype modulation, epigenetic editing also offers opportunities for off-the-shelf donor-derived CAR T cells by enabling stable silencing of immune rejection pathways, thereby addressing key barriers to their clinical application. This review highlights the pivotal role of epigenetic regulation in T cell biology and CAR T cell therapy, and explores how epigenetic drugs, genetic interventions, and emerging epigenetic editing strategies can be harnessed to generate more potent, persistent, and widely accessible CAR T cell therapies.

Keywords:  CAR-T; CRISPR; Epigenetics; TALE; ZFP

DOI:  https://doi.org/10.1186/s13148-026-02085-1
bioRxiv. 2026 Feb 13. pii: 2026.02.12.705596. [Epub ahead of print]

IFN-driven lipid synthesis shutdown in CD4⁺ T cells during acute SIV infection and persistent OXPHOS with ART initiation.

Jinhee Kim, Anoop Ambikan, Jakob Harrison-Gleason, Kayla L Yerlioglu, Iva Filipovic, Romaila Abdelraouf, Catarina Ananias-Saez, Erin B Taylor, Mariluz Arainga, Deepanwita Bose, Francois J Villinger, Ujjwal Neogi, Elena Martinelli.

Cellular metabolism regulates HIV/SIV replication and reservoir establishment, yet how infection and antiretroviral therapy initiation (ARTi) shape the metabolism of CD4⁺ Tcells-main HIV target- in vivo remains poorly defined. Using the SIVmac239 macaque model, we integrated single-cell metabolic profiling (MIST), transcriptomics, lipidomics, genome-scale metabolic modeling, and functional assays to characterize their metabolic remodeling. At peak viremia, CD4⁺ T cells exhibited a marked shutdown of de novo fatty-acid (FA) synthesis, reflected by acetyl-CoA carboxylase-1 (ACC1) downregulation, inhibition of lipid-anabolic reactions, and depletion of membrane phospholipids. This metabolic state was driven by strong type I interferon (IFN-I) responses, and IFN-I exposure was sufficient to suppress ACC1 in vitro . Pharmacologic inhibition of FA synthesis independently enhanced Tcell activation and reduced HIV replication, indicating direct antiviral and immunomodulatory effects. Following ARTi, most metabolic pathways were broadly suppressed, whereas mitochondrial oxidative phosphorylation (OXPHOS) remained elevated. Together, these findings identify IFN-driven FA synthesis shutdown and persistent OXPHOS as defining metabolic features of early HIV/SIV infection and treatment initiation, highlighting these pathways as potential targets to limit viral replication and reservoir formation.

DOI: https://doi.org/10.64898/2026.02.12.705596
ACS Omega. 2026 Feb 17. 11(6): 9671-9685

T Cell Receptor Co-Stimulation Through Magnetogenetic Tools: A Platform for Wireless Rewiring of Cellular Signaling.

Seyed Hossein Helalat, Rodrigo C Téllez, Helga Thora Kristinsdóttir, Astrid Dolinger Petersen, Islam Seder, Carlos Rodriguez Pardo, Yi Sun.

Synthetic biology offers innovative strategies to control cell function for therapeutic applications. Here, we present a magnetogenetic platform for T cell receptor (TCR) costimulation using magnetic fields to achieve noninvasive activation of T cells. We employed engineered TRPV1, TRPV4, and electromagnetic perceptive gene (EPG) constructs in HEK293, Jurkat, and primary human T cells. Calcium imaging confirmed functional activation of these tools, while qPCR and proteomic analyses revealed downstream effects on activation markers, calcium signaling, mitochondrial function, and membrane integrity. In Jurkat and primary T cells, magnetic stimulation alone reduced activation signatures, but when combined with antigenic stimulation, it significantly enhanced T cell activation. This dual-modality response indicates that magnetogenetic tools can serve as tunable costimulators of TCR signaling. Our findings highlight the potential of wireless, magnetically controlled systems to precisely modulate immune cell behavior, with implications for the development of next-generation cell-based immunotherapies.

DOI: https://doi.org/10.1021/acsomega.5c10000