Cellular and Molecular Mechanisms of CD8+ T Cell Differentiation, Dysfunction and Exhaustion

Abstract

T cells follow a triphasic distinct pathway of activation, proliferation and differentiation before becoming functionally and phenotypically "exhausted" in settings of chronic infection, autoimmunity and in cancer. Exhausted T cells progressively lose canonical effector functions, exhibit altered transcriptional networks and epigenetic signatures and gain constitutive expression of a broad coinhibitory receptor suite. This review outlines recent advances in our understanding of exhausted T cell biology and examines cellular and molecular mechanisms by which a state of dysfunction or exhaustion is established, and mechanisms by which exhausted T cells may still contribute to pathogen or tumour control. Further, this review describes our understanding of exhausted T cell heterogeneity and outlines the mechanisms by which checkpoint blockade differentially engages exhausted T cell subsets to overcome exhaustion and recover T cell function.

Keywords: PD-1; T cell exhaustion; cancer; chronic viral infections; epigenetics; immunotherapy; inhibitory receptors.

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.

Figure 2

T_PEX respond to anti-PD-1/PD-L1 blockade. TCF-1^HI intratumoral or virus-specific precursor-exhausted T cells (T_PEX) expressing intermediate surface levels of PD-1 continually replenish and maintain a pool of cytotoxic granzyme B^HI TCF-1^NEG PD-1^HI TIM-3^HI exhausted progeny (T_EX) when they are stimulated. PD-1:PD-L1 interactions impair activation and proliferation of T_PEX and activation cytokine production and direct cytotoxicity of T_EX. Blockade of these interactions using monoclonal antibodies allows the expansion of a larger tumour- or virus-reactive T_EX pool, and enhances direct cytotoxicity against transformed or virus-infected cells.