Transcription Factor T-bet Represses Expression of the Inhibitory Receptor PD-1 and Sustains Virus-Specific CD8+ T Cell Responses During Chronic Infection

Nat Immunol. 2011 May 29;12(7):663-71. doi: 10.1038/ni.2046.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / immunology*
  • Antigens, Viral / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / 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

Substances

  • Antigens, Differentiation
  • Antigens, Viral
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • T-Box Domain Proteins
  • T-box transcription factor TBX21

Grant support