Figure 1.

Acute and chronic infection drive distinct programs of CD8⁺ T cell differentiation. Activated naïve CD8⁺ cells initiate a program of metabolic, transcriptional and epigenetic changes that facilitate differentiation into KLRG1^HI CD127^neg effector and KLRG1^neg CD127^HI memory precursors (MPEC). In an acute infection, an expanded pool of terminally differentiated cytotoxic effectors (SLEC/T_EFF) clear infected cells and subsequently contract, leaving behind a heterogeneous pool of MPEC-derived self-renewing stem-like (T_SCM) and central memory (T_CM) in secondary lymphoid organs and effector memory (T_EM) and resident memory (T_RM) in peripheral tissues to provide protection against secondary exposure to the same pathogen. Chronic TCR stimulation, exacerbated by the absence of appropriate CD4⁺ T cell “help” and co-stimulatory and cytokine signalling, drives an alternative program of differentiation and epigenetic remodeling mediated by NFATc1, BATF, IRF4 and Tox. This gives rise to a TCF-1⁺PD-1^INT pool of self-renewing “precursor” exhausted cells carrying a distinct epigenetic signature (T_PEX) that produce and continually replenish an expanded pool of terminally exhausted progeny (T_EX) able to partially control, but not fully clear, established infection. T_EX maintain the epigenetic signature established in T_PEX and exhibit a spectrum of effector function impairment and high expression of a suite of co-inhibitory receptors.