T Cell Exhaustion as a Regulated Differentiation Programme

T cell exhaustion is now recognised as a structured, antigen-driven differentiation programme rather than a state of cellular fatigue. Under sustained antigen exposure, CD8⁺ T cells progress through distinct, hierarchically organised differentiation states, initiated by progenitor exhausted cells (T_PEX), which retain self-renewal, multipotency, and responsiveness to immune checkpoint blockade. Continued stimulation drives differentiation into intermediate (T_EXint) and terminally exhausted (T_{EX term}) states, with T_EXint retaining greater effector capacity than T_EXterm despite both exhibiting restraint relative to functional effector T cells, alongside increasingly consolidated epigenetic architecture. Rather than reflecting immunological failure, exhaustion preserves long-term antigen surveillance while limiting tissue damage. Convergence between exhaustion-associated transcriptional modules and tissue-resident memory (T_RM) programmes highlights shared mechanisms of adaptation to restrictive microenvironments. Yet T_RM and T_EX arise in distinct contexts and are not interchangeable. Recognising exhaustion as a context-dependent differentiation process reframes therapeutic strategies, in line with current evidence indicating that immune checkpoint blockade primarily acts by expanding and redirecting the T_PEX pool rather than reversing terminal exhaustion. This framework integrates insights from chronic infection, tumour immunology, and tissue adaptation.