Molecular Dissection of CD8⁺ T-Cell Dysfunction

Chronic viral infections and cancer often lead to the emergence of dysfunctional or 'exhausted' CD8⁺ T cells, and the restoration of their functions is currently the focus of therapeutic interventions. In this review, we detail recent advances in the annotation of the gene modules and the epigenetic landscape associated with T-cell dysfunction. Together with analysis of single-cell transcriptomes, these findings have enabled a deeper and more precise understanding of the transcriptional mechanisms that induce and maintain the dysfunctional state and highlight the heterogeneity of CD8⁺ T-cell phenotypes present in chronically inflamed tissue. We discuss the relevance of these findings for understanding the transcriptional and spatial regulation of dysfunctional T cells and for the design of therapeutics.