From Dysfunction to Differentiation: A New Paradigm of T Cell Exhaustion

CD8⁺ T cell exhaustion is the loss of certain functions typical of cytotoxic lymphocytes. CD8⁺ cytotoxic T cells originate from naive CD8⁺ T cells upon antigen exposure. Chronic or excessive antigen exposure during certain infections and cancers triggers inhibitory mechanisms that lead to functional exhaustion - a loss of the ability to secrete IFN-γ and other cytokines, as well as to produce granzyme- and perforin-containing lytic granules in response to stimulation. Functional exhaustion also affects CD4⁺ helper T cells, which further reduces CD8⁺ T cell cytotoxicity. This leads to the loss of the CD8⁺ T cell's ability to kill target cells, which negatively impacts immunity and reduces the efficacy of therapeutic T cells. Currently, T cell exhaustion is considered as a multistage, partially reversible differentiation program. Heterogeneous subsets of stem-like progenitor exhausted T cells (Tex-prog) and terminally exhausted T cells (Tex-term) have been identified. These cells differ in their degrees of dysfunction and, thus, in their potential to restore lost functions. The transcriptional exhaustion program is controlled by key transcription factors, such as TCF1, TOX, T-bet, EOMES, BATF, IRF4, etc. Understanding the dynamic changes taking place in the transcriptional profile and cellular phenotype is critical for effective immunotherapy, in particular in immune checkpoint blockade (ICB) and CAR-T cell therapy, because its success depends entirely on the T cell state. In this review, we discuss current concepts on the molecular and cellular mechanisms of T cell exhaustion, various exhaustion-associated phenotypic and functional changes, and opportunities for preventing T cell exhaustion to optimize anti-tumor immunotherapy strategies.