Immune regulation through mitochondrion-dependent dendritic cell death induced by T regulatory cells

J Immunol. 2011 Dec 1;187(11):5684-92. doi: 10.4049/jimmunol.1101834. Epub 2011 Oct 26.

Abstract

Dendritic cells (DCs) harbor an active mitochondrion-dependent cell death pathway regulated by Bcl-2 family members and undergo rapid turnover in vivo. However, the functions for mitochondrion-dependent cell death of DCs in immune regulation remain to be elucidated. In this article, we show that DC-specific knockout of proapoptotic Bcl-2 family members, Bax and Bak, induced spontaneous T cell activation and autoimmunity in mice. In addition to a defect in spontaneous cell death, Bax(-/-)Bak(-/-) DCs were resistant to killing by CD4(+)Foxp3(+) T regulatory cells (Tregs) compared with wild-type DCs. Tregs inhibited the activation of T effector cells by wild-type, but not Bax(-/-)Bak(-/-), DCs. Bax(-/-)Bak(-/-) DCs showed increased propensity for inducing autoantibodies. Moreover, the autoimmune potential of Bax(-/-)Bak(-/-) DCs was resistant to suppression by Tregs. Our data suggested that Bax and Bak mediate intrinsic spontaneous cell death in DCs, as well as regulate DC killing triggered by Tregs. Bax- and Bak-dependent cell death mechanisms help to maintain DC homeostasis and contribute to the regulation of T cell activation and the suppression of autoimmunity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • Apoptosis / immunology*
  • Autoimmunity / immunology*
  • Cell Separation
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Flow Cytometry
  • Immunohistochemistry
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Knockout
  • Self Tolerance / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • bcl-2 Homologous Antagonist-Killer Protein / immunology
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-2-Associated X Protein / immunology
  • bcl-2-Associated X Protein / metabolism

Substances

  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein