Determinants of T Cell Exhaustion: How Far Back Can We Go?

Over the past four decades, T cell exhaustion has been primarily associated with chronic infection and cancer and described as a late, adaptive response that limits immunopathology under chronic antigen exposure. Emerging evidence has revealed that exhausted T (Tex) cells are formed developmentally with distinct transcriptomic, epigenetic and phenotypic profiles, with progressive and hierarchical loss of effector functions. Recent reports show that exhaustion is not merely a late-stage phenomenon, but a multifaceted developmental trajectory that begins far earlier than previously thought. Intrinsic factors established at T cell priming synergize with extrinsic cues from the tissue microenvironment to drive T cell differentiation towards an exhausted state long before exhaustion becomes phenotypically fixed. This review presents an overview of recent knowledge that has reshaped our understanding of T cell exhaustion formation. Here, we discuss the genetic, epigenetic and metabolic determinants of T cell exhaustion, as well as the roles other soluble mediators and cell types may play in promoting exhaustion. Enhancing our understanding of early determinants of exhaustion has implications for the development and application of therapeutic strategies that adapt to the temporal evolution of exhaustion, which may be more effective than treatments aimed solely at reversing exhaustion.