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PMID: 21623380 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature immunology ·Vol. 12 ·No. 7 ·2011-05-29 ·Pages 663-71

Kao C, Oestreich KJ, Paley MA, Crawford A, Angelosanto JM, Ali MA, Intlekofer AM, Boss JM, Reiner SL, Weinmann AS, Wherry EJ

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.

MeSH Terms
Animals Antigens, Differentiation/genetics,immunology Antigens, Viral/immunology CD4-Positive T-Lymphocytes/immunology CD8-Positive T-Lymphocytes/immunology,metabolism Chronic Disease Lymphocyte Activation/immunology Lymphocytic Choriomeningitis/immunology Lymphocytic choriomeningitis virus/immunology Mice Mice, Inbred C57BL Programmed Cell Death 1 Receptor T-Box Domain Proteins/immunology Transcription, Genetic/immunology
Chemicals
Antigens, Differentiation Antigens, Viral Pdcd1 protein, mouse Programmed Cell Death 1 Receptor T-Box Domain Proteins T-box transcription factor TBX21
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Kao Charlly
Department of Microbiology and Institute for Immunology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Oestreich Kenneth J
Paley Michael A
Crawford Alison
Angelosanto Jill M
Ali Mohammed-Alkhatim A
Intlekofer Andrew M
Boss Jeremy M
Reiner Steven L
Weinmann Amy S
Wherry E John
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Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.2046
Published
2011-05-29
Epub
2011-00-29
Pages
663-71
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC3306165
Subset
IM
Grants
NIAID NIH HHS · U19 AI083022 · United States
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External Links
PubMed source DOI: 10.1038/ni.2046 PMC Full Text View journal details
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