Targeting the fate of exhausted CD8+ T cells.

Immune checkpoint blockade enhances CD4 effector function to control persistent viral infection 2267612

T cell exhaustion, a defining hallmark of chronic viral infections and cancer, is characterized by the progressive loss of effector function and sustained expression of inhibitory receptors on T cells. Although immune checkpoint blockade (ICB) therapies, such as PD-1 inhibition, can transiently reinvigorate subsets of exhausted CD8+ T cells, their efficacy remains constrained by the limited pool of self-renewing, progenitor-like TCF1+ CXCR5+ CD8+ T cells. We have previously demonstrated that B cell—derived IL-27 signaling is necessary for the expansion and maintenance of this progenitor-like population during chronic infection. Using an IL-27 receptor deficient mouse model, we reveal a previously unrecognized mechanism by which PD-1 blockade mediates viral clearance. We demonstrate that PD-1 inhibition enhances CD4+ T cell function, specifically through increased IL-21 production from T follicular helper (Tfh) cells which promotes both humoral and cytotoxic antiviral responses. Our findings identify a novel IL-27 independent CD4+ T cell axis through which checkpoint blockade controls persistent viremia. To determine the impact of checkpoint inhibition on persistent viral infection, IL-27 receptor—deficient mice were infected with chronic lymphocytic choriomeningitis virus (LCMV clone 13) and treated with PD-1 blocking antibodies. We used flow cytometry and viral titers to evaluate CD4+ and CD8+ T cell subsets, the importance of IL-21, and persistent viral clearance. PD-1 blockade restored antiviral immunity in IL-27 receptor—deficient mice and resulted in enhanced CD4+ T cell function. We saw increased IL-21 production from T follicular helper cells that led to higher cytotoxic and humoral antiviral responses. Our studies reveal that PD-1 blockade can drive persistent viral clearance through an IL-27—independent mechanism that involves IL-21—producing CD4+ T cells. N/A Viral Immunology (VIR)

Antigen dependency defines memory and exhausted CD8 T cell fates 2257447

Antigen experienced T cell subsets are heterogenous, and can be described based on their phenotype, function, and migration properties. We wished to better understand how antigen stimulation regulates the trafficking, survival, differentiation and developmental plasticity of T cell subsets. We developed a new mouse model that allows for the in vivo excision of the P14 TCR on a defined fraction of antigen-specific CD8 T cells. Specifically, we engineered a novel tamoxifen-inducible TCR-knockout transgenic mouse using a rAAV6 vector encoding for the floxed P14 TCR gene. This model allows for permanent cessation of antigen stimulation on select T cells at time points of our choosing. After acute infection with LCMV Armstrong, elimination of the TCR on established memory CD8 T cells maintained stable subset composition, but resulted in detectable downregulation of exhaustion markers, indicating that TCR sensing occurs among steady-state memory T cells. TCR deletion during chronic infections (LCMV Minnesota and LCMV Cl13 ± aCD4 depletion) affected both the population structure and phenotype. Terminal (Tex/TXt), as well as progenitor exhausted (Tpex/TXp) T cell subsets substantially declined after TCR deletion in persistently viremic infection with LCMV Cl13 + aCD4. However, the loss of Tpex/TXp after TCR deletion was moderated in settings of chronic infections without CD4 T cell depletion, in which most host viral load was more tightly controlled. These results demonstrate that the antigen dependence of Tpex/TXp depends on context, and a subset may survive in the absence of further antigen stimulation, which has important implications for maintaining immunity to chronic infections and cancer. Walter Benjamin Program, DFG Lymphocyte Differentiation and Peripheral Maintenance (LYM)

Mathematical modeling of T cell exhaustion in the tumor microenvironment.

T cell exhaustion (TCE), a hallmark of chronic infections and cancer, is characterized by progressive loss of effector function, sustained expression of inhibitory receptors, and stable transcriptional/epigenetic reprogramming. Within the tumor microenvironment (TME), exhausted CD8+ T cells fail to eliminate malignant cells, contributing to immune evasion and resistance to immunotherapy. Although checkpoint blockade has provided clinical benefit, outcomes remain variable, underscoring the need to better understand the temporal and mechanistic basis of exhaustion. Current modeling efforts have yielded valuable insights; however, they often focus on isolated aspects of tumor-immune interactions. Deterministic models such as ordinary, partial, and delay differential equations capture population dynamics, but omit stochastic variation and single-cell heterogeneity. Stochastic and agent-based models address randomness and spatial structure at a greater computational cost. Hybrid and multiscale approaches increasingly integrate these methods, but few explicitly capture the progressive, time-series nature of TCE as revealed by recent epigenetic and transcriptomics studies. This review analyzes various mathematical and computational frameworks including deterministic, stochastic, and hybrid approaches that have been applied to study TCE in viral and cancer contexts. We distinguish between TCE-specific models that directly represent exhaustion dynamics and TCE-relevant frameworks that model tumor-immune interactions, spatial tumor microenvironment features, and pharmacological interventions that could be adapted to optimize future TCE models. By comparing strengths and limitations across frameworks, we identify key gaps including limited integration of temporal resolution, lack of multiscale intracellular regulation, and scarce validation with longitudinal experimental data. We also highlight how TCE-relevant models can support pharmacological and translational questions, including dose optimization, pharmacokinetic /pharmacodynamic (PK/PD) integration, and mechanisms of immunotherapy failure. Future models that adopt hybrid, time-resolved, and multiscale designs linking intracellular regulatory networks, population-level signaling, and spatially heterogeneous TME features, calibrated with time-series omics data, would be invaluable in addressing these gaps. Such frameworks would provide mechanistic insights into exhaustion trajectories, supporting advances in immunotherapy design and clinical outcomes.

Targeting T-cell exhaustion and tumour immune evasion: a review of emerging strategies.

A complementary therapeutic strategy is discussed: engineering T cells for greater durability in the TME through knockout of exhaustion-associated transcription factors, and reprogramming tumour cells with DNA methyltransferase (DNMTi) and histone deacetylase (HDACi) inhibitors to restore immunogenicity.

A novel microbial-derived metabolite counteracts exhaustion programming in CD8 T cells 2260531

These findings identify a novel microbial SCFA as a potential metabolic-epigenetic regulator, capable of reactivating effector programs in TEX cells while blocking terminal exhaustion, and provide insights into developing new therapeutic approaches to reprogram TEX cells and enhance the efficacy of T cell immunotherapy.

PD-1⁺ CD8⁺ T cells: roles of PD-1 beyond an exhaustion marker