T-cell exhaustion

T-cell exhaustion is a hypofunctional state acquired by antigen-specific T lymphocytes — primarily CD8+ cytotoxic T cells — under persistent antigen exposure, such as chronic viral infection (HIV, HBV, HCV) or tumour antigens. Effector functions are lost hierarchically: IL-2 secretion fails first, followed by TNF-α, then IFN-γ; proliferative capacity and cytolytic activity diminish progressively. Exhausted T cells co-express multiple inhibitory checkpoint receptors — PD-1, TIM-3, LAG-3, CTLA-4 — defining the immunophenotype; Wherry et al. (2007, Immunity) mapped these receptors alongside metabolic and TCR-signalling defects in chronic LCMV clone-13 infection. Sustained TCR signalling activates calcineurin/NFAT2, inducing the HMG-box transcription factor TOX; Khan et al. (2019, Nature) showed TOX locks in an exhaustion-specific chromatin landscape through epigenetic remodelling, making the state largely irreversible and only partially rescuable by PD-1/TIM-3 checkpoint blockade. Exhaustion is distinct from T-cell senescence: senescent cells carry permanent replicative arrest with SA-β-gal and p16/p21 upregulation, whereas exhausted T cells retain residual proliferative potential. CMV seropositivity — present in ~40–80% of older adults — drives clonal inflation of Tim-3+PD-1+ T cells accumulating even without active infection (Lee et al., 2016, Aging Cell). In oncology, exhaustion depth in tumour-infiltrating lymphocytes predicts checkpoint-blockade response, since TOX-driven epigenetic fixation limits reinvigoration.