Acquired Transcriptional Programming in Functional and Exhausted Virus-specific CD8 T Cells

• Authors: Benjamin Alan Youngblood, Emory University; E. John Wherry, University of Pennsylvania; Rafi Ahmed, Emory University
• Journal Title: Current Opinion in HIV and AIDS
• Volume: Volume 7, Number 1
• Publisher: Lippincott, Williams & Wilkins | 2012-01, Pages 50-57
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1097/COH.0b013e32834ddcf2
• Subjects: Biology, Microbiology; Health Sciences, Immunology
• Keywords: Chronic Infection; CD8 T cell; Exhaustion; Transcription Factor; Epigenetic

Abstract

Purpose of Review Failure to control viral infections such as HIV, results in TCR and inhibitory receptor driven exhaustion of antigen-specific T cells. Persistent signaling by these receptors during chronic viral infection sculpts the transcriptional regulatory programs of virus-specific T cells. The resulting gene expression profile is tailored to temper the potentially damaging effector functions of cytotoxic T cells and adapt them to an antigen and inflammation rich environment. Here we review recent studies investigating mechanisms of transcriptional regulation of effector, functional memory, and exhausted T cell functions during acute versus chronic infections. Recent Findings Patterns of gene expression in virus-specific CD8 T cells are a result of a combination of pro and inhibitory signals from antigen presentation (TCR-mediated) and co-inhibitory receptor ligation (PD-1, 2B4). Further, memory-specific transcriptional regulation of 2B4 expression and signaling impose a self-limiting secondary effector response to a prolonged viral infection. Additionally, differentiation of functional memory CD8 T cells is coupled to acquisition of a repressive epigenetic program for PD-1 expression. However, chronic infection provides a signal which blocks the acquisition of these epigenetic modifications reinforcing the suppression of CTL functions in exhausted cells. Summary Current findings suggest that the mechanism(s) that delineate functional memory versus exhaustion are coupled to acquisition of transcriptional programs at the effector stage of differentiation, reinforced by cessation or persistence of TCR signaling.