A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection

Immunity. 2009 Aug 21;31(2):309-20. doi: 10.1016/j.immuni.2009.06.019. Epub 2009 Aug 6.

Abstract

T cell exhaustion is common during chronic infections and can prevent optimal immunity. Although recent studies have demonstrated the importance of inhibitory receptors and other pathways in T cell exhaustion, the underlying transcriptional mechanisms are unknown. Here, we define a role for the transcription factor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Blimp-1 repressed key aspects of normal memory CD8(+) T cell differentiation and promoted high expression of inhibitory receptors during chronic infection. These cardinal features of CD8(+) T cell exhaustion were corrected by conditionally deleting Blimp-1. Although high expression of Blimp-1 fostered aspects of CD8(+) T cell exhaustion, haploinsufficiency indicated that moderate Blimp-1 expression sustained some effector function during chronic viral infection. Thus, we identify Blimp-1 as a transcriptional regulator of CD8(+) T cell exhaustion during chronic viral infection and propose that Blimp-1 acts as a transcriptional rheostat balancing effector function and T cell exhaustion.

Publication types

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

MeSH terms

  • Acute Disease
  • Animals
  • Antigens, CD / immunology
  • Antigens, CD / metabolism
  • Antigens, Surface / immunology
  • Antigens, Surface / metabolism
  • Apoptosis Regulatory Proteins / immunology
  • Apoptosis Regulatory Proteins / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / virology
  • Cell Differentiation / immunology
  • Chronic Disease
  • Cytotoxicity, Immunologic / immunology
  • GPI-Linked Proteins
  • Granzymes / immunology
  • Granzymes / metabolism
  • Immunologic Memory / immunology*
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Positive Regulatory Domain I-Binding Factor 1
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic / immunology
  • Receptors, Immunologic / metabolism
  • Signaling Lymphocytic Activation Molecule Family
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Virus Diseases / genetics
  • Virus Diseases / immunology*

Substances

  • Antigens, CD
  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • CD223 antigen
  • Cd160 protein, mouse
  • Cd244a protein, mouse
  • GPI-Linked Proteins
  • Pdcd1 protein, mouse
  • Prdm1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic
  • Signaling Lymphocytic Activation Molecule Family
  • Transcription Factors
  • Positive Regulatory Domain I-Binding Factor 1
  • Granzymes