Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8(+) T cell responses during chronic infection

• Type of Material: Article
• Authors: Carlly Kao, University of Pennsylvania; Kenneth J. Oestreich, University of Washington; Michael A. Paley, University of Pennsylvania; Alison Crawford, University of Pennsylvania; Jill M. Angelosanto, University of Pennsylvania; Mohammed-Alkhatim A. Ali, University of Pennsylvania; Andrew M. Intlekofer, University of Pennsylvania; Jeremy Boss, Emory University; Steven L. Reiner, University of Pennsylvania; Amy S. Weinmann, University of Washington; E. John Wherry, University of Pennsylvania
• Language: English
• Date: 2011-07-01
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Nature America, Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/ni.2046
• Title of Journal or Parent Work: Nature Immunology
• ISSN: 1529-2908
• Volume: 12
• Issue: 7
• Start Page: 663
• End Page: U117
• Grant/Funding Information: This work was supported by an NIH training grant (AI007518 to CK) and grants from the NIH/NIAD (AI071309, AI082630, AI083022, HHSN266200500030C to EJW; AI061699, AI076458 to SLR), the Foundation for NIH and Grand Challenge in Global Health (to EJW), and the Dana Foundation (to EJW).
• Keywords: TIM-3; Science & Technology; ACTIVATION; Life Sciences & Biomedicine; CHRONIC VIRAL-INFECTION; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; Immunology; EXHAUSTION; DIFFERENTIATION; ELEVATED FREQUENCIES; INTERFERON-GAMMA; DISEASE PROGRESSION; PROGRAMMED DEATH-1
• Research Categories: Biology, Microbiology; Health Sciences, Immunology

Abstract

T cell exhaustion has a major role in failure to control chronic infection. High expression of inhibitory receptors, including PD-1, and the inability to sustain functional T cell responses contribute to exhaustion. However, the transcriptional control of these processes remains unclear. Here we demonstrate that the transcription factor T-bet regulated the exhaustion of CD8+ T cells and the expression of inhibitory receptors. T-bet directly repressed transcription of the gene encoding PD-1 and resulted in lower expression of other inhibitory receptors. Although a greater abundance of T-bet promoted terminal differentiation after acute infection, high T-bet expression sustained exhausted CD8+ T cells and repressed the expression of inhibitory receptors during chronic viral infection. Persistent antigenic stimulation caused downregulation of T-bet, which resulted in more severe exhaustion of CD8+ T cells. Our observations suggest therapeutic opportunities involving higher T-bet expression during chronic infection.