Receptor signaling, transcriptional, and metabolic regulation of T cell exhaustion

Exhaustion cripples T cell effector responses against metastatic cancers and chronic infections alike. There has been considerable interest in understanding the molecular and cellular mechanisms driving T cell exhaustion in human cancers fueled by the success of immunotherapy drugs especially the checkpoint receptor blockade (CRB) inhibitory antibodies that reverses T cell functional exhaustion. The current understanding of molecular mechanism of T cell exhaustion has been elucidated from the studies utilizing murine models of chronic viral infections. These studies have formed the basis for much of our understanding of the process of exhaustion and proven vital to developing anti-exhaustion therapies against human cancers. In this review, we discuss the T cell exhaustion differentiation pathway in cancers and chronic viral infections and explore how the transcription factors expression dynamics play role in T cell exhaustion fate choices and maturation. Finally, we summarize the role of some of the most important transcription factors involved in T cell functional exhaustion and construct exhaustion specific signaling pathway maps.