Transcriptional regulation and T cell exhaustion

This review highlights the control of transcriptional networks, including induction of inhibitory receptors, by T cell-specific transcription factors in exhausted T cells that accumulate in chronic viral infections including HIV.

Transcriptional profiling has established distinct molecular phenotypes for exhausted CD4 and CD8 T cells in chronic viral infection models. There exists a subset of transcription factors associated with exhaustion, notably Blimp-1, basic leucine zipper transcription factor, ATF-like and Helios. Epigenetic phenomena are likely important in regulating gene expression networks during exhaustion as illustrated by programmed death 1 promoter methylation patterns.

Following chronic viral infections, CD4 and CD8 T cells defined functionally and phenotypically as exhausted have distinct transcriptional profiles. These studies have identified a core set of transcription factors that have been implicated in promoting exhaustion. However, no single factor appears to be an exhaustion determining factor, suggesting that T cell exhaustion reflects a combinatorial mechanism with multiple transcription factors interacting to influence the development of functionally exhausted T cells as well as different T effector populations.