title: Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection.
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.
authors.affiliation: Department of Microbiology and Institute for Immunology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Charlly
authors.initials: C
authors.lastname: Kao
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Oestreich
authors.forename: Michael A
authors.initials: MA
authors.lastname: Paley
authors.forename: Alison
authors.initials: A
authors.lastname: Crawford
authors.forename: Jill M
authors.initials: JM
authors.lastname: Angelosanto
authors.forename: Mohammed-Alkhatim A
authors.initials: MA
authors.lastname: Ali
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Intlekofer
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Boss
authors.forename: Steven L
authors.initials: SL
authors.lastname: Reiner
authors.forename: Amy S
authors.initials: AS
authors.lastname: Weinmann
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D008213:Lymphocyte Activation / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor; D020825:T-Box Domain Proteins / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D000943:Antigens, Differentiation; D000956:Antigens, Viral; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor