Bid and Bim collaborate during induction of T cell death in persistent infection

J Immunol. 2011 Apr 1;186(7):4059-66. doi: 10.4049/jimmunol.1001918. Epub 2011 Feb 21.

Abstract

Upon Ag encounter, naive T cells undergo extensive Ag-driven proliferation and can differentiate into effector cells. Up to 95% of these cells die leaving a small residual population of T cells that provide protective memory. In this study, we investigated the contribution of the BH3-only family protein Bid in the shutdown of T cell responses after acute and persistent infection. Influenza virus pathogenicity has been proposed to be mediated by a peptide encoded in the basic polymerase (PB1-RF2) acting through Bid. In our experiments, we found that after acute infection with influenza virus, mice lacking Bid had normal expansion and contraction of Ag-specific CD8(+) T cells. However, in chronic γ-herpesvirus infection, Bid-deficient virus-specific CD8(+) T cells expanded normally but failed to contract fully and were maintained at ∼2-fold higher levels. Previously, we have demonstrated that Bim plays a prominent role in T cell shutdown in persistent infection by cooperating with the death receptor Fas, which regulates apoptosis in response to repeated TCR signaling. Bid lies at the nexus of these two signaling pathways, thus we reasoned that Bid and Bim might cooperate in regulation of T cell shutdown in persistent infection. In this study, we observed that the combined loss of Bid and Bim synergistically enhanced the persistence of CD8(+) T cells during γ-herpesvirus infection. Thus, these data uncover a role for Bid in coordinating apoptotic signaling pathways to ensure appropriate shutdown of T cell immune responses in the setting of persistent Ag exposure.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology*
  • Apoptosis Regulatory Proteins / physiology*
  • BH3 Interacting Domain Death Agonist Protein / physiology*
  • Bcl-2-Like Protein 11
  • Cell Communication / immunology
  • Cell Death / immunology
  • Herpesviridae Infections / immunology*
  • Herpesviridae Infections / metabolism
  • Herpesviridae Infections / pathology*
  • Influenza A Virus, H3N2 Subtype / immunology
  • Lymphocyte Cooperation / immunology*
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / metabolism
  • Orthomyxoviridae Infections / pathology
  • Proto-Oncogene Proteins / physiology*
  • Rhadinovirus / immunology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / pathology*
  • T-Lymphocyte Subsets / virology
  • Tumor Virus Infections / immunology
  • Tumor Virus Infections / metabolism
  • Tumor Virus Infections / pathology
  • Viral Load / immunology

Substances

  • Apoptosis Regulatory Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • Bid protein, mouse
  • Membrane Proteins
  • Proto-Oncogene Proteins