Acquired transcriptional programming in functional and exhausted virus-specific CD8 T cells.

TitleAcquired transcriptional programming in functional and exhausted virus-specific CD8 T cells.
Publication TypeJournal Article
Year of Publication2012
AuthorsYoungblood B, Wherry JE, Ahmed R
JournalCurr Opin HIV AIDS
Volume7
Issue1
Pagination50-7
Date Published2012 Jan
ISSN1746-6318
KeywordsAntigens, Viral, CD8-Positive T-Lymphocytes, Gene Expression Profiling, Gene Expression Regulation, HIV, Humans, Immunologic Memory, Transcription, Genetic
Abstract

PURPOSE OF REVIEW: Failure to control viral infections such as HIV results in T-cell receptor (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-rich 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 with acquisition of a repressive epigenetic program for PD-1 expression. However, chronic infection provides a signal that blocks the acquisition of these epigenetic modifications reinforcing the suppression of cytotoxic lymphocyte (CTL) functions in exhausted cells.

SUMMARY: Current findings suggest that the mechanism(s) that delineate functional memory versus exhaustion are coupled with acquisition of transcriptional programs at the effector stage of differentiation, reinforced by cessation or persistence of TCR signaling.

DOI10.1097/COH.0b013e32834ddcf2
Alternate JournalCurr Opin HIV AIDS
PubMed ID22134341