bims-imseme 2025-08-10 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2025–08–10
23 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.
Mechanisms of T-cell metabolic reprogramming in the microenvironment of acute myeloid leukemia and its therapeutic potential (Review).
Diet-derived galactose reprograms hepatocytes to prevent T cell exhaustion and elicit antitumour immunity.
Metabolic checkpoints in immune cell reprogramming: rewiring immunometabolism for cancer therapy.
Multi-omics integration analysis identifies INPP4B as a T-cell-specific activation suppressor.
Multi-omics profiling identifies TNFRSF18 as a novel marker of exhausted CD8⁺ T cells and reveals tumour-immune dynamics in colorectal cancer.
Antigen reactivity defines tissue-resident memory and exhausted T cells in tumours.
Mitochondria reactive oxygen species signaling-dependent immune responses in macrophages and T cells.
The transcription factor BATF pioneers the differentiation program of effector CD8+ T cells through the interaction with IRF4.
Asymmetry and redundancy of STAT5 paralogs across CD8 + T cell differentiation states.
CD4+ T cell dysfunction in cancer.
Metabolic landscape uncovers remodeling of T cell immunity affected by fatty acid desaturase in Parkinson's disease at single-cell resolution.
Programmable microparticles rewire CAR signaling to enable super-physiological expansion of human T cells in vitro.
Themis differentially regulates T follicular helper cell differentiation during early and late stages of chronic viral infection.
Delineating the short- and long-term impact of ionizing radiation on antigen-inexperienced CD8+ T cell subsets.
Pan-cancer single cell transcriptomic clustering reveals heterogeneous CD8+ exhausted T cell populations with different immune checkpoint inhibitor responses.
Regulatory T cells epigenetically reprogrammed from autoreactive effector T cells mitigate established autoimmunity.
Single-cell map of the healthy human immune system across the lifespan reveals unique infant immune signatures.
Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline.
Nicotinamide phosphoribosyltransferase in NAD+ metabolism: physiological and pathophysiological implications.
Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target.
Regulation of CD45 isoforms during human effector and memory CD8 T cell differentiation: Implications for T cell nomenclature.
Design of soluble Notch agonists that drive T cell development and boost immunity.

Cell Metab. 2025 Jul 30. pii: S1550-4131(25)00333-X. [Epub ahead of print]

Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.

Joseph Longo, Lisa M DeCamp, Brandon M Oswald, Robert Teis, Alfredo Reyes-Oliveras, Michael S Dahabieh, Abigail E Ellis, Michael P Vincent, Hannah Damico, Kristin L Gallik, Nicole M Foy, Shelby E Compton, Colt D Capan, Kelsey S Williams, Corinne R Esquibel, Zachary B Madaj, Hyoungjoo Lee, Dominic G Roy, Connie M Krawczyk, Brian B Haab, Ryan D Sheldon, Russell G Jones.

  Glucose is essential for T cell proliferation and function, yet its specific metabolic roles in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8+ T cell expansion and cytotoxic function in vivo. Using 13C-based stable isotope tracing, we demonstrate that CD8+ effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis. Inhibiting GSL production by targeting the enzymes UDP-Glc pyrophosphorylase 2 (UGP2), UDP-Gal-4-epimerase (GALE), or UDP-Glc ceramide glucosyltransferase (UGCG) impairs CD8+ T cell expansion upon pathogen challenge. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and optimal T cell receptor (TCR) signaling. Moreover, UGCG-deficient CD8+ T cells display reduced granzyme expression, cytolytic activity, and tumor control in vivo. Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose-beyond energy production-that is required for CD8+ T cell responses in vivo.

Keywords:  CD8(+) T cells; UGCG; cytotoxic function; glucose; glycosphingolipids; immunometabolism; lipid rafts; lipidomics; metabolomics; nucleotide sugar metabolism

DOI:  https://doi.org/10.1016/j.cmet.2025.07.006
Oncol Lett. 2025 Oct;30(4): 455

Mechanisms of T-cell metabolic reprogramming in the microenvironment of acute myeloid leukemia and its therapeutic potential (Review).

Yanhong Luo, Jie Luo, Min Yang, Xueya Zhao.

  Acute myeloid leukemia (AML) is an aggressive hematological malignancy that is often resistant to conventional therapies. The present narrative review discusses on the role of T cell metabolic reprogramming in the AML tumor microenvironment (TME), which markedly impacts the effectiveness of immunotherapy. The TME of AML, influenced by factors such as high lactic acid (LA) levels, hypoxia and nutrient competition, hampers T cell functions such as glycolysis, lipid metabolism and amino acid metabolism, leading to impaired T cell proliferation and antitumor response. Metabolic waste products, including LA and adenosine, further contribute to the immunosuppressive environment. T cell exhaustion, induced by nutrient deprivation and metabolic dysregulation, serves a key role in the failure of immune responses. Moreover, strategies to modulate T cell metabolism, such as targeting glycolysis and fatty acid oxidation, show promise in enhancing immunotherapy outcomes. The current review also highlights emerging technologies, such as single-cell metabolomics and CRISPR screening, which are critical for identifying metabolic targets and advancing personalized therapies. Despite challenges in translating these findings to clinical settings, understanding T cell metabolism in the AML TME offers new therapeutic avenues for improving patient outcomes.

Keywords:  T cells; immunization; tumor immunology

DOI:  https://doi.org/10.3892/ol.2025.15201
Nat Cell Biol. 2025 Aug 08.

Diet-derived galactose reprograms hepatocytes to prevent T cell exhaustion and elicit antitumour immunity.

Xian Du, Wenyan Li, Guiying Li, Chenyue Guo, Xuyi Tang, Rujuan Bao, Runchang Li, Haiyan Huang, Shuiyu Xu, Xiaoyan Yu, Qiaoqiao Han, Jie Wan, Song Li, Jiayuan Sun, Ren Zhao, Youqiong Ye, Qiang Gao, Zhi-Yu Ni, Xingang Cui, Qiang Zou.

Dietary nutrients are inextricably linked to antitumour immune responses. However, the effect of diet-derived galactose on antitumour immunity remains unclear. Here we show that dietary galactose augments CD8+ T cell immunity to suppress tumour progression. High-galactose feeding drives hepatocyte-derived insulin-like growth factor binding protein 1 (IGFBP-1) production, thus restraining IGF-1 signalling-dependent T cell exhaustion. IGF-1 receptor (IGF-1R) deficiency in T cells potentiates antitumour CD8+ T cell responses and phenocopies high-galactose feeding by preventing T cell exhaustion. Circulating galactose reprograms hepatocyte metabolism to inactivate mTORC1, thereby inducing the production of IGFBP-1 to boost CD8+ T cell function. Furthermore, patients with cancer who have high plasma IGFBP-1 levels exhibit blocked T cell exhaustion and enhanced T cell responses in tumour tissues. These findings reveal that dietary galactose specifically elicits potent antitumour CD8+ T cell responses by facilitating hepatocyte-derived IGFBP-1 production, providing insights into the development of more effective immunotherapies against cancers.

DOI: https://doi.org/10.1038/s41556-025-01716-8
Mol Cancer. 2025 Aug 02. 24(1): 210

Metabolic checkpoints in immune cell reprogramming: rewiring immunometabolism for cancer therapy.

Yingying Lv, Zongshang Li, Shutong Liu, Zhaokai Zhou, Jinling Song, Yuhao Ba, Siyuan Weng, Anning Zuo, Hui Xu, Peng Luo, Quan Cheng, Chuhan Zhang, Jingyuan Ning, Yukang Chen, Yuyuan Zhang, Zaoqu Liu, Xinwei Han.

  Immune cell metabolism plays a pivotal role in regulating cellular proliferation, differentiation, and functional responses, collectively shaping immune responses within the tumor microenvironment (TME). Recent advancements increasingly highlight diverse metabolic phenotypes of immune cells and their complex interplay with tumor dynamics. Immune cell metabolism exhibits remarkable plasticity, enabling metabolic networks to finely tune immune cell behaviors in response to external stimuli. Furthermore, a strong correlation between metabolic profiles and immune cell fate, activation, and function has been repeatedly delineated in immunometabolism. Consequently, targeting the metabolic networks, referred to as metabolic checkpoints, to reprogram immune cell phenotypes and bolster antitumor immunity holds significant promise for clinical translation. This review summarizes the latest developments in multifaceted metabolic checkpoints, with a focus on how metabolic checkpoints modulate immunological consequences and cancer progression. Lastly, potential strategies for targeting metabolic checkpoints are explored to inspire innovative approaches in immunotherapy.

Keywords:  Cancer immunotherapy; Immune cells; Metabolic checkpoints; Metabolic reprogramming; T cell; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-025-02407-6
Clin Transl Med. 2025 Aug;15(8): e70430

Multi-omics integration analysis identifies INPP4B as a T-cell-specific activation suppressor.

Ting Peng, Qing Fang, Zihao Zhao, Yingjun Chang, Xiangyu Zhao, Cheng Li.

   BACKGROUND: Naïve T cells are maintained in a quiescent state prior to activation. As inappropriate T-cell activation can lead to impaired immune tolerance and autoimmune diseases, the transition from quiescence to activation must be under strict regulation. Despite its importance, the mechanisms underlying the maintenance of the quiescent state remain incompletely understood.
METHODS AND RESULTS: Through multi-omics integration analysis, we reveal that INPP4B, a phosphatase of the phosphoinositide 3-kinase pathway, is highly expressed specifically in T cells and is involved in suppressing T-cell activation and maintaining quiescence. Our findings uncover that INPP4B forms a T-cell-specific chromatin interaction domain and exhibits high expression levels in quiescent T cells. Upon T-cell activation, both the chromatin interaction and expression levels of INPP4B decrease. Functional studies further confirm that INPP4B suppresses T-cell activation and effector functions. Additionally, we observe increased expression level of INPP4B in exhausted T cells within the tumour microenvironment.
CONCLUSION: These results highlight the importance of maintaining optimal levels of INPP4B for T-cell function. Our findings suggest that INPP4B could be a potential target for enhancing the efficacy of T-cell-mediated immune responses against tumours.
KEY POINTS: A comprehensive multi-omics analysis characterizes the expression patterns of INPP4B across immune populations. INPP4B exhibits a T-cell-specific expression domain and functions as a T cell activation suppressor. INPP4B is significantly upregulated in exhausted T cells within the tumour microenvironment.

Keywords:  INPP4B; T‐cell activation; multi‐omics

DOI:  https://doi.org/10.1002/ctm2.70430
Clin Transl Med. 2025 Aug;15(8): e70425

Multi-omics profiling identifies TNFRSF18 as a novel marker of exhausted CD8⁺ T cells and reveals tumour-immune dynamics in colorectal cancer.

Tengfei Jia, Yingxi Guo, Xin Meng Cheng, Zeyang Zhou, Xiaojiang Xu, Hebin Liu, Xiaodong Yang.

   BACKGROUND: Colorectal cancer (CRC) ranks among the most prevalent malignant tumours of the digestive system globally and is associated with unfavourable survival outcomes. The exhaustion of CD8⁺ T cells serves a crucial role in facilitating tumour immune escape. Yet, the dynamic evolution of CD8⁺ T cell exhaustion and its impact on clinical prognosis across TNM (tumour-node-metastasis) stages in CRC remains incompletely characterized.
METHODS: Tumour and adjacent tissues (20 samples total) from 6 CRC patients spanning diverse TNM stages were analyzed using integrated single-cell transcriptomic profiling (scRNA-seq), single-cell T cell receptor/B cell receptor sequencing (scVDJ-seq), and spatial transcriptomics. T cell exhaustion markers, immune clonality, gene expression profiles, and the spatial distribution of both tumour cells and immune cells were systematically profiled. Functional enrichment and intercellular communication analyses were conducted. Key findings were validated using immunofluorescence and public datasets.
RESULTS: Our results illustrate how advancing TNM stages in CRC shape CD8⁺ T cell exhaustion through divergent TNFRSF18/CXCL13 dynamics and ribosomal stemness. TNFRSF18 expression was notably higher in T cells infiltrating tumour tissues relative to their counterparts in adjacent non-tumorous areas, with high-expressing CD8⁺ T cells exhibiting marked exhaustion features. During CRC progression, TNM-stage-driven remodelling of the tumour microenvironment (TME) induced progressive CD8⁺ T cell exhaustion marked by declining TNFRSF18 and rising CXCL13 expression in tumour-infiltrating T cells elevation of both markers in the tumour compared with adjacent tissues. Moreover, we show that tumour cells displayed elevated expression of stemness-associated ribosomal genes (RPS7, RPL8, RPL30), peaking at stage T4, which correlated with poor prognosis and immune escape.
CONCLUSIONS: This integrative multi-omics study uncovers CD8⁺ T cell exhaustion dynamics and ribosomal stemness-mediated immune evasion across CRC progression. CXCL13, TNFRSF18, and ribosomal proteins (RPS7/RPL8/RPL30) are identified as novel biomarkers with direct prognostic value and therapeutic relevance, providing therapeutic targets for precision immunotherapy in CRC.
KEY POINTS: Multi-omics analysis reveals dynamic CD8+ T cell exhaustion patterns across CRC samples with different TNM stages. TNFRSF18 is highly expressed in exhausted tumour-infiltrating CD8+ T cells and declines with disease progression. Ribosomal stemness in tumour cells promotes immune evasion by impairing TNF-mediated CD8+ T cell function.

Keywords:  T cell exhaustion; TNFRSF18 (GITR); TNM stage; colorectal cancer; singlecell RNA sequencing; spatial transcriptomics

DOI:  https://doi.org/10.1002/ctm2.70425
bioRxiv. 2025 Jul 23. pii: 2025.07.23.666465. [Epub ahead of print]

Antigen reactivity defines tissue-resident memory and exhausted T cells in tumours.

Thomas N Burn, Jan Schröder, Luke C Gandolfo, Maleika Osman, Elanor N Wainwright, Enid Y N Lam, Keely M McDonald, Rachel B Evans, Shihan Li, Daniel Rawlinson, Lachlan Dryburgh, Ali Zaid, Zoltan Maliga, Dominick Schienstock, Philippa Meiser, Hyun Jae Lee, Hongjin Lai, Marcela L Moreira, Pirooz Zareie, Louis H-Y Lee, Lutfi Huq, Susan N Christo, Justine J W Seow, Keith A Ching, Stéphane M Guillaume, Kathy Knezevic, Simone L Park, Maximilien Evrard, Jason Waithman, Thomas Gebhardt, Scott N Mueller, Georgina E Riddiough, Marcos V Perini, Simon C H Tsao, Terence P Speed, Peter K Sorger, Sherene Loi, Francis R Carbone, Stephanie Gras, Timothy S Fisher, Bas J Baaten, Mark A Dawson, Laura K Mackay.

CD8 + T cells are a key weapon in the therapeutic armamentarium against cancer. While CD8 + CD103 + T cells with a tissue-resident memory T (T RM ) cell phenotype have been favourably correlated with patient prognoses 1-6 , the tumour microenvironment also contains dysfunctional exhausted T (T EX ) cells that exhibit a myriad of T RM -like features, leading to conflation of these two populations. Here, we deconvolute T RM and T EX cells within the intratumoural CD8 + CD103 + T cell pool across human cancers, ascribing markers and gene signatures that distinguish these CD8 + populations and enable their functional distinction. We found that while T RM cells exhibit superior functionality and are associated with long-term survival post-tumour resection, they are not associated with responsiveness to immune checkpoint blockade. Deconvolution of the two populations showed that tumour-associated T EX and T RM cells are clonally distinct, with the latter comprising both tumour-independent bystanders and tumour-specific cells segregated from their cognate antigen. Intratumoural T RM cells can be forced towards an exhausted fate when chronic antigen stimulation occurs, arguing that the presence or absence of continuous antigen exposure within the microenvironment is the key distinction between respective tumour-associated T EX and T RM populations. These results suggest unique roles for T RM and T EX cells in tumour control, underscoring the need for distinct strategies to harness these T cell populations in novel cancer therapies.

DOI: https://doi.org/10.1101/2025.07.23.666465
Immunity. 2025 Jul 29. pii: S1074-7613(25)00321-8. [Epub ahead of print]

Mitochondria reactive oxygen species signaling-dependent immune responses in macrophages and T cells.

Samuel E Weinberg, Navdeep S Chandel.

Mitochondria are key regulators of immune cell function, going beyond their traditional role in ATP and metabolite production to support anabolic processes and act as hubs for intracellular signaling. A key aspect of this signaling function is the production of mitochondrial reactive oxygen species (mtROS), which act as critical second messengers in both adaptive and innate immune regulation. Immune cells maintain an optimal concentration of mtROS to maintain physiological responses, and excessive or lack of mtROS production contributes to chronic inflammation, autoimmunity, and cancer. Here, we review the molecular mechanisms controlling mtROS production and detoxification, their role in shaping macrophage and T cell fate and function, and their implications for disease pathogenesis.

DOI: https://doi.org/10.1016/j.immuni.2025.07.012
Cell Rep. 2025 Aug 06. pii: S2211-1247(25)00900-3. [Epub ahead of print]44(8): 116129

The transcription factor BATF pioneers the differentiation program of effector CD8+ T cells through the interaction with IRF4.

Sotaro Fujisawa, Yamato Tanabe, Arisa Hojo, Ryotaro Shiga, Junko Kurachi, Miki Koura, Toshikatsu Tamai, Yusuke Miyanari, E John Wherry, Makoto Kurachi.

  Basic leucine zipper transcription factor ATF-like (BATF) plays a crucial role in CD8+ T cell (CTL) differentiation. Here, we demonstrated that BATF controls epigenomic and transcriptomic reprogramming of CTLs at the early stages of acute viral infection, thereby promoting effector CTL differentiation. Loss of BATF drastically perturbed gene expression, chromatin accessibility, and binding of key transcription factors. The BATF-interferon regulatory factor 4 (IRF4) interaction was essential for BATF-mediated effector differentiation, as the BATF mutant lacking this interaction failed to induce proper chromatin remodeling and proliferation of antigen-specific CTLs. Notably, IRF4 binding thoroughly depended on BATF, whereas BATF retained binding capacity even in IRF4-deficient CTLs. Furthermore, BATF initiated chromatin remodeling without IRF4; however, subsequent dynamic epigenomic reorganization required IRF4. These findings suggest that BATF serves as a "pioneer transcription factor" spearheading chromatin reorganization upon antigen encounter. This fundamental role is followed by further rearrangement of epigenomic and transcriptomic landscapes through the cooperation with IRF4.

Keywords:  BATF; CD8(+) T cell differentiation; CP: Immunology; IRF4; chromatin landscape

DOI:  https://doi.org/10.1016/j.celrep.2025.116129
bioRxiv. 2025 Jul 28. pii: 2025.07.23.666302. [Epub ahead of print]

Asymmetry and redundancy of STAT5 paralogs across CD8 + T cell differentiation states.

Svetlana Ristin, Molly Dalzell, Christopher Armstrong, Nisa Ilsin, Antonio M Fontanella, Luis Nivelo, Lothar Hennighausen, John J O'Shea, Alejandro V Villarino.

Fostering STAT5 signaling is key to immunotherapies that leverage CD8 + T cell biology. Using mouse models, we demonstrate that the two mammalian STAT5 paralogs, STAT5A and STAT5B, are at once redundant and functionally distinct in CD8 + T cells. Specifically, we establish that they are asymmetric paralogs , exhibiting both widespread homology at molecular level and functional asymmetry at cellular level, with STAT5B emerging as dominant. In fact, compared to STAT5A, STAT5B deficiency had greater impact on nearly all parameters tested. As a mechanism, we determined STAT5B is twice as abundant, accounting for two-thirds of the total STAT5 pool. We also defined both cytokine- and cell state-restricted STAT5B functions, and a core gene signature that highlights universal effects. Together, these studies affirm the centrality of STAT5 in CD8 + T cells, reveal common and circumscribed activities, and present a unifying model for paralog redundancy that foregrounds and explains the dominance of STAT5B. Summary : STAT5 paralog dominance and redundancy in CD8 + T cells.

DOI: https://doi.org/10.1101/2025.07.23.666302
J Exp Med. 2025 Sep 01. pii: e20241417. [Epub ahead of print]222(9):

CD4+ T cell dysfunction in cancer.

Hrishi Venkatesh, Lawrence Fong.

While the importance of CD8+ T cells in successful cancer immunotherapy is well-established, CD4+ T cells are increasingly recognized as key mediators of effective anti-tumor immunity. However, the mechanisms underlying the functional impairment of CD4+ T cells in tumors are not as well characterized as in CD8+ T cells. In this review, we will explore how CD4+ T cells are altered in tumor-bearing hosts, compare these changes to those observed in CD8+ T cells, and discuss how these changes impact tumor control. Approaches that counteract functional impairment in tumor-reactive CD4+ T cells may further enhance the efficacy of cancer immunotherapy.

DOI: https://doi.org/10.1084/jem.20241417
BMC Biol. 2025 Aug 06. 23(1): 245

Metabolic landscape uncovers remodeling of T cell immunity affected by fatty acid desaturase in Parkinson's disease at single-cell resolution.

Shi Yan, Xue Zhao, Yao Si, Xinyu Zhang, Di Wang, Lifen Yao, Linlin Sun.

   BACKGROUND: Peripheral activated T cells cross the blood-brain barrier, partake in neuroinflammation, and induce dopaminergic neuron degeneration through characteristics such as cell adhesion and immune response in Parkinson's disease (PD). Metabolic activity, which can regulate and be regulated by cellular signaling pathways, has a profound impact on the differentiation and function of T cells. However, a characterization of T-cell metabolic heterogeneity at single-cell resolution in PD is still lacking. Here, combining metabolic gene expression profiling and pathway activity algorithm, we studied the metabolic programs in PD-associated T cells.
RESULTS: Cytotoxic T cells (CTLs) with adhesive properties dominated the proportion in PD patients based on the distribution of T cell types at single-cell resolution. The unsaturated fatty acid (UFA) biosynthetic process was found to be the pivotal contributor to CTLs' metabolic features distinct from other cell types. Meanwhile, the upregulation of UFA biosynthetic process strongly correlated with immunologic activity in CTLs. Additionally, we revealed that fatty acid desaturases became the critical factor in determining CTLs' metabolic heterogeneity according to the differentiation of T cell lineage and the high expression of metabolic genes in PD. Subsequent fatty acid desaturases adjustments mediated crosstalk with CTLs' immunity, suggesting a potential target for regulating neuroinflammation in PD condition.
CONCLUSIONS: This analysis decoded the activation of T cells from another perspective, where PD-associated CTLs were metabolically reprogrammed to interact with the immune system, for in-depth insights into the immune characteristics of PD.

Keywords:  Metabolic reprogramming; Parkinson’s disease; T cells; Unsaturated fatty acid biosynthetic process; scRNA-seq

DOI:  https://doi.org/10.1186/s12915-025-02358-w
bioRxiv. 2025 Jul 22. pii: 2025.07.17.665438. [Epub ahead of print]

Programmable microparticles rewire CAR signaling to enable super-physiological expansion of human T cells in vitro.

Qinghe Zeng, Landon Flemming, Yuanzhou Chen, Thomas Mazumder, Heinz Hammerlindl, Greg M Allen, Ricardo Almeida, Jasper Z Williams, Rogelio A Hernández-López, Justin Eyquem, Chun J Ye, Wendell A Lim, Qizhi Tang, Tejal A Desai, Xiao Huang.

T cell proliferative capacity and persistence critically determine the therapeutic success of chimeric antigen receptor (CAR) T cells. However, it remains unknown if and how human CAR-T cells can be externally programmed to reach maximal proliferative capacity. Here, we use programmable PLGA microparticles functionalized with CAR-antigens and CD28-costimulatory antibodies (CAREp) to repeatedly stimulate human CD8 + CAR-T cells in vitro . CAREp-stimulated CAR-T cells expanded continuously for over 100 days-versus ∼30 days with tumor cell stimulation-and achieved up to 10 18 -fold cumulative expansion, greatly surpassing CD3/28-Dynabeads. Early-phase transcriptomic responses- upregulation of DNA repair, cell cycle, telomere maintenance, and mitochondrial pathways-aligned with long-term outcomes: massive proliferation, telomere stability, robust respiration, and preserved progenitor phenotype by single-cell sequencing. Differentiation and exhaustion signals were broadly suppressed. Transient telomerase activity further supported physiologic expansion. These findings demonstrate that nanoscale-controlled extracellular cues can rewire intracellular signaling to drive durable, super-physiological expansion of functional CAR-T cells.

DOI: https://doi.org/10.1101/2025.07.17.665438
Front Immunol. 2025 ;16 1638178

Themis differentially regulates T follicular helper cell differentiation during early and late stages of chronic viral infection.

Yuzhen Zhu, Yuzhou Bao, Ning Wang, Qifeng Gan, Jian Tang, Yu Cong, Bowen Hou, Minxue Quan, Chaonan Yan, Siyi Liu, Shuo Lin, Xiaobin Zhang, Yanping Du, Lichao Hou, Nicholas R J Gascoigne, Bing Xu, Guo Fu, Qifan Zheng.

   Introduction: T follicular helper (TFH) cells are critical for humoral immunity during chronic viral infection, but the mechanisms guiding their differentiation from a novel CD4⁺ T cell progenitors remain incompletely understood. Themis, a T cell-specific adaptor protein, has been implicated in T cell development and function, but its role in peripheral CD4⁺ T cell differentiation under chronic antigen stimulation has not been defined.
Methods: We used a chronic lymphocytic choriomeningitis virus (LCMV) Clone13 infection model in wild-type and Themis conditional knockout (cKO) mice. A combination of adoptive cell transfer, flow cytometry, histological analysis, and single-cell RNA sequencing (scRNA-seq) was applied to analyze the differentiation of CD4⁺ T cells into TFH cells at multiple infection stages.
Results: Themis expression is strongly upregulated in TFH cells at early stages of infection, and as expected, Themis promotes TFH cell differentiation at this stage. However, unexpectedly, at the late stages of chronic LCMV infection, Themis-deficient CD4+ T cells favored TFH cell differentiation and helped control the virus by enhancing GC responses and antibody production, suggesting that Themis inhibits TFH cell differentiation at this stage. In the late stage we found that Themis inhibits the differentiation of CD4+ T cell progenitors into TFH cells through transcriptional regulation.
Discussion: Our study uncovers a dual-stage regulatory role of Themis in TFH cell differentiation during chronic viral infection. While promoting TFH generation early, Themis unexpectedly restrains excessive differentiation at later stages, suggesting its function is context- and time-dependent. These findings highlight Themis as a key temporal regulator of CD4⁺ T cell fate decisions under chronic antigenic stress.

Keywords:  CD4 + T cell progenitor; GC responses; THEMIS; Tfh cells; chronic viral infection

DOI:  https://doi.org/10.3389/fimmu.2025.1638178
JCI Insight. 2025 Aug 05. pii: e194201. [Epub ahead of print]

Delineating the short- and long-term impact of ionizing radiation on antigen-inexperienced CD8+ T cell subsets.

Mohammad Heidarian, Shravan K Kannan, Whitney Swanson, Thomas S Griffith, John T Harty, Vladimir P Badovinac.

  Radiation-induced lymphopenia (RIL) remains a challenging side effect of radiation therapy, often associated with poor prognosis and reduced overall survival. Although CD8+ T cells are highly radiosensitive, the dynamics of quantitative and qualitative changes to the CD8 T cell pool following exposure to high doses of ionizing radiation (IR) remains understudied. Herein, we sought to determine the long-term impact of sublethal whole body irradiation (WBI) on antigen (Ag)-inexperienced CD8 T cell pool, comprised of naïve (TN) and virtual memory (TVM) CD8+ T cells. We show that although both TN and TVM cells gradually regenerate after WBI-induced loss, TN recovery only occurs through de novo thymic production. Despite the numerical restoration, the subset and phenotypic composition of post-recovery Ag-inexperienced CD8+ T cells do not qualitatively recapitulate the pre-WBI state. Specifically, the frequency of TVM cells is increased, especially during the early stages of recovery. Within the TN subset, a lasting overrepresentation of Ly6C+CD122+ cells and an altered TCR clonotype diversity are also observed. Overall, our data highlight the dynamic changes to the Ag-inexperienced CD8+ T cell pool upon recovery from RIL.

Keywords:  Immunology; Inflammation; Radiation therapy; T cells

DOI:  https://doi.org/10.1172/jci.insight.194201
Oncoimmunology. 2025 Dec;14(1): 2540504

Pan-cancer single cell transcriptomic clustering reveals heterogeneous CD8+ exhausted T cell populations with different immune checkpoint inhibitor responses.

Rui Mu, Rasha Barakat, David H Gutmann.

  In most cancers, T lymphocytes comprise an essential cellular component of the non-neoplastic microenvironment, where they have the capacity to both suppress and support tumor growth. One specialized T lymphocyte population is the CD8+ exhausted T cell, which has been intensely studied as an actionable therapeutic target. Unfortunately, there is currently no uniformly accepted classification scheme for these specialized T cells. To provide a potential model for classifying CD8+ exhausted T cells, we leveraged single cell transcriptomic analysis of a diverse collection of both human (n = 8) and mouse (n = 4) cancers to identify unique subpopulations shared across tumor types and species. By integrating data from both human and mouse cancer studies, as well as previously described CD8+ exhausted T cell subsets, we provide an integrated framework to characterize the heterogeneity of exhausted CD8+ T cells. As such, one of these subpopulations (cluster C1) increases following immune checkpoint inhibitor treatment in the setting of cancer in mice and patients. Taken together, this proposed classification scheme may be useful for the design and interpretation of current and future immune-based therapy studies.

Keywords:  CD8+ T cells; Cancer; exhaustion; immune checkpoint inhibitor; transcriptomics

DOI:  https://doi.org/10.1080/2162402X.2025.2540504
bioRxiv. 2025 Jul 28. pii: 2025.07.24.665398. [Epub ahead of print]

Regulatory T cells epigenetically reprogrammed from autoreactive effector T cells mitigate established autoimmunity.

Tyler R Colson, James J Cameron, Hayley I Muendlein, Mei-An Nolan, Jamie L Leiriao, James H Kim, Alexander N Poltorak, Xudong Li.

Reprogramming autoreactive CD4 + effector T (T eff ) cells into immunosuppressive regulatory T (T reg ) cells represents a promising strategy for treating established autoimmune diseases. However, the stability and function of such reprogrammed T regs under inflammatory conditions remain unclear. Here, we show that demethylation of core T reg identity genes in T eff cells yields lineage-stable Effector T cell Reprogrammed T regs (ER-T regs ). A single adoptive transfer of ER-T regs not only prevents autoimmune neuroinflammation in mice when given before disease onset but also arrests its progression when administered after onset. Compared to Foxp3-overexpressing T eff cells, induced T regs from naïve precursors, and endogenous T regs , ER-T regs provide superior protection against autoimmune neuroinflammation. This enhanced efficacy stems from their inherited autoantigen specificity and selectively preserved effector-cell transcriptional programs, which together bolster their fitness in inflammatory environments and enhance their suppressive capacity. Our results establish epigenetic reprogramming of autoreactive T eff cells as an effective approach to generate potent, stable T regs for the treatment of refractory autoimmune conditions.

DOI: https://doi.org/10.1101/2025.07.24.665398
bioRxiv. 2025 Jul 31. pii: 2025.07.28.667181. [Epub ahead of print]

Single-cell map of the healthy human immune system across the lifespan reveals unique infant immune signatures.

Djamel Nehar-Belaid, Asa Thibodeau, Alper Eroglu, Radu Marches, Giray Eryilmaz, Derya Unutmaz, Chris P Verschoor, Jinghua Gu, Uthra Balaji, Asunción Mejías, Virginia Pascual, George A Kuchel, Octavio Ramilo, Jacques F Banchereau, Duygu Ucar.

The human immune system undergoes continuous remodeling from infancy through old age, yet the timing and trajectory of these changes across the lifespan remain poorly defined. To address this, we profiled peripheral blood mononuclear cells from 95 healthy individuals (ages 2 months to 88 years), including infants (n=27), children (n=23), adults (n=18), and older adults (n=27) using scRNA-seq and snATAC-seq. MAIT and γδ T cells showed a "Rise and fall" pattern, which rise in childhood, peak in young adulthood, and decline with age. CD8 + T cells were the most affected by aging with decreasing naïve T cells and increasing GzK + CD8 + T cells and TEMRA cells. Infants had lower myeloid/lymphoid ratio, with a distinct composition marked by increased frequencies of CD16 + monocytes and plasmacytoid dendritic cells and reduced frequencies of CD14 + monocytes and conventional DCs. Their adaptive immune compartment also displayed unique features, including constitutive interferon-stimulated gene expression in T and B cells, and an expanded SOX4 + populations in naïve CD4 + , naïve CD8 + and γδ T cells, comprising ∼30% of the naïve T cell pool. SOX4 + naïve CD4 + T cells displayed a Th2 epigenetic signature. This map provides critical insights into human immune system dynamics across the lifespan, emphasizing unique features of the infant immune system.

DOI: https://doi.org/10.1101/2025.07.28.667181
bioRxiv. 2025 Aug 02. pii: 2025.08.01.668243. [Epub ahead of print]

Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline.

Adarsh Rajesh, Aaron P Havas, Rouven Arnold, Kathryn Lande, K Garrett Evensen, Kelly Yichen Li, Sainath Mamde, Qian Yang, Armin Gandhi, Karl N Miller, Marcos Garcia Teneche, Zoe Yao, Jessica Proulx, Andrew Davis, Laurence Haddadin, Michael Alcaraz, Carolina Cano Macip, Brightany Li, Xue Lei, Charlene Miciano, Elizabeth Smoot, Allen Wang, Jeffrey H Albrecht, April E Williams, Bing Ren, Kevin Y Yip, Peter D Adams.

Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in these non-proliferating cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments (CCFs) that activate pro-inflammatory CGAS-STING signaling. The tumor suppressor p53 (TP53) and its target p21 (CDKN2A) antagonize this CCND1-CDK6-dependent DNA damage accumulation pathway to suppress the SASP. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the Cdk4/6 inhibitor Palbociclib reduces DNA damage and ISGs in aged mouse liver. Notably, Palbociclib also suppresses frailty and improves physical performance of aged mice. These findings reveal a novel role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising therapeutic target.

DOI: https://doi.org/10.1101/2025.08.01.668243
Cell Death Discov. 2025 Aug 08. 11(1): 371

Nicotinamide phosphoribosyltransferase in NAD+ metabolism: physiological and pathophysiological implications.

Weijia Zhang, Haoyu Ren, Wangwang Chen, Bo Hu, Chao Feng, Peishan Li, Yufang Shi, Jiankai Fang.

Nicotinamide adenine dinucleotide (NAD⁺) is a critical coenzyme involved in cellular metabolism, energy balance, and various physiological processes. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme in NAD⁺ synthesis, regulating the NAD⁺ regeneration pathway. This review summarizes the multiple roles of NAMPT in both physiological and pathological states, particularly in cellular stress, aging, metabolic disorders, and cancer. We first describe the central role of NAMPT in NAD⁺ synthesis and explore how NAD⁺ levels are regulated through NAMPT to control cellular functions and metabolic adaptation. Second, we analyze the pathological roles of NAMPT in aging and related diseases, highlighting how NAD⁺ depletion leads to mitochondrial dysfunction, DNA damage, and immune system dysregulation. Notably, NAMPT exacerbates cancer immune evasion mechanisms by influencing immune cell functions and the metabolic environment of tumors. We also discuss the potential of NAMPT as a therapeutic target, particularly through NAD⁺ precursor supplementation or the use of NAMPT activators and inhibitors to modulate NAD⁺ metabolism in aging, metabolic diseases, and cancer. Future research should focus on exploring the functional differences of NAMPT in various tissues and its therapeutic potential in disease treatment.

DOI: https://doi.org/10.1038/s41420-025-02672-w
Nat Commun. 2025 Aug 07. 16(1): 7271

Integrative multi-omics reveals a regulatory and exhausted T-cell landscape in CLL and identifies galectin-9 as an immunotherapy target.

L Llaó-Cid, Jkl Wong, I Fernandez Botana, Y Paul, M Wierz, L-M Pilger, A Floerchinger, C L Tan, S Gonder, G Pagano, M Chazotte, K Bestak, C Schifflers, M Iskar, T Roider, F Czernilofsky, P-M Bruch, J P Mallm, A Cosma, D E Campton, E Gerhard-Hartmann, A Rosenwald, D Colomer, E Campo, D Schapiro, E W Green, S Dietrich, P Lichter, E Moussay, J Paggetti, M Zapatka, M Seiffert.

T-cell exhaustion contributes to immunotherapy failure in chronic lymphocytic leukemia (CLL). Here, we analyze T cells from CLL patients' blood, bone marrow, and lymph nodes, as well as from a CLL mouse model, using single-cell RNA sequencing, mass cytometry, and tissue imaging. T cells in CLL lymph nodes show the most distinct profiles, with accumulation of regulatory T cells and CD8+ T cells in various exhaustion states, including precursor (TPEX) and terminally exhausted (TEX) cells. Integration of T-cell receptor sequencing data and use of the predicTCR classifier suggest an enrichment of CLL-reactive T cells in lymph nodes. Interactome studies reveal potential immunotherapy targets, notably galectin-9, a TIM3 ligand. Inhibiting galectin-9 in mice reduces disease progression and TIM3+ T cells. Galectin-9 expression also correlates with worse survival in CLL and other cancers, suggesting its role in immune evasion and potential as a therapeutic target.

DOI: https://doi.org/10.1038/s41467-025-61822-x
Proc Natl Acad Sci U S A. 2025 Aug 12. 122(32): e2322982122

Regulation of CD45 isoforms during human effector and memory CD8 T cell differentiation: Implications for T cell nomenclature.

Donald J McGuire, Rama S Akondy, Shu Yang, Srilatha Edupuganti, Shashi Nagar, Garett Michael, Stephen C De Rosa, Evan W Newell, Donna L Farber, Haydn T Kissick, M Juliana McElrath, Rafi Ahmed.

  This study examines the expression of CD45 isoforms on human yellow fever virus vaccine (YFV-17D) specific CD8 T cells longitudinally after vaccination. As expected, effector CD8 T cells at day 14 express CD45RO but within 4 to 6 wk these virus-specific CD8 T cells become CD45RA positive and remain CD45RA for >10 y. The journey for these YFV-specific CD8 T cells goes from naive (CD45RA+ CCR7+) to effector/effector memory (CD45RO+ CCR7-) to Temra (CD45RA+ CCR7-) to stem-cell memory (CD45RA+ CCR7+). These YFV-specific CD8 T cells rarely acquire the canonical Tcm phenotype (CD45RO+ CCR7+). This CD45RO to RA switch coincides with clearance of YFV, so we hypothesized that antigen may be playing a role in regulating CD45 expression. We addressed this issue by ex vivo analysis and provide evidence that this switch is indeed regulated by antigen. Sorted YFV-specific CD45RO effector CD8 T cells reexpress CD45RA when cultured ex vivo in the absence of antigen and retain CD45RO in the presence of cognate peptide. We also extended these ex vivo analysis to human cytomegalovirus (CMV)-specific CD8 T cells and show that CD45RO cells transition to CD45RA in the absence of antigen and CD45RA cells become CD45RO when stimulated with CMV peptide. We then show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific CD8 T cells can repeatedly undergo the same CD45RA to RO to RA transition in vivo after the SARS-CoV-2 mRNA vaccination. Again, the canonical Tcm phenotype spike-specific memory CD8 T cells were not readily detectable. These studies warrant a reevaluation of how human memory CD8 T cells are defined.

Keywords:  CD45 isoforms; Human CD8 T cell nomenclature; SARS-CoV-2; cytomegalovirus; yellow fever vaccine

DOI:  https://doi.org/10.1073/pnas.2322982122
Cell. 2025 Jul 29. pii: S0092-8674(25)00798-6. [Epub ahead of print]

Design of soluble Notch agonists that drive T cell development and boost immunity.

Rubul Mout, Ran Jing, Mayuri Tanaka-Yano, Emily D Egan, Helen Eisenach, Martin A Kononov, Roland Windisch, Mohamad Ali Toufic Najia, Allison Tompkins, Luca Hensch, Trevor Bingham, Rajesh Gunage, Yunliang Zhao, Natasha I Edman, Christopher Li, Dahai Wang, Thorsten M Schlaeger, Leonard I Zon, Trista E North, Urban Lendahl, R Grant Rowe, David Baker, Stephen C Blacklow, George Q Daley.

  The rational design of receptor agonists to control cell signaling is an emerging strategy for developing disease therapeutics. Creating a soluble cytokine-like agonist for the Notch receptor, which regulates cell fate in embryonic and adult development, is challenging, as receptor activation requires a mechanical force that is usually mediated by cell-associated transmembrane ligands. Here, we exploit computationally designed protein complexes with precise valencies and geometries to generate soluble cytokine-like Notch agonists. These molecules promote cell-cell bridging, cluster Notch receptors at cell synapses, and activate receptor signaling. We show that these agonists drive T cell differentiation from cord blood progenitors and human induced pluripotent stem cells (iPSCs) and in bioreactor production of T cells in liquid suspension. When delivered intravenously in mice, they stimulate cytokine production, expansion of antigen-specific CD4+ T cells, and antibody class switching. These de-novo-designed ligands can be broadly applied to optimize in vitro cell differentiation and advance immunotherapy development.

Keywords:  Notch signaling; T cell development; T cell immunity; computational protein design; iPSC-derived T cells; immunotherapy; protein agonist; soluble Notch activation; vaccine

DOI:  https://doi.org/10.1016/j.cell.2025.07.009