Origins and functional basis of regulatory CD11c+CD8+ T cells

Eur J Immunol. 2009 Jun;39(6):1552-63. doi: 10.1002/eji.200839057.

Abstract

Previously, we showed that CD11c defines a novel subset of CD8(+) T cells whose in vivo activity is therapeutic for arthritis; however, the mechanisms directing their development, identity of their precursors, and basis of their effector function remain unknown. Here, we show that the novel subset develops from CD11c(surface-)CD8(+) T cells and undergoes robust expansion in an antigen- and 4-1BB (CD137)-dependent manner. CD11c(+)CD8(+) T cells exist in naïve mice (<3%) with limited suppressive activity. Once activated, they suppress CD4(+) T cells in vivo and in vitro. Suppression of CD4(+) by CD11c(+)CD8(+) T cells is related to an increase in IDO activity induced in competent cells via the general control non-derepressible-2 pathway. CD11c(+)CD8(+) T cells are refractory to the effect of IDO but constrict in a novel 1-methyl D,L-tryptophan-dependent mechanism resulting in reversal of their suppressive effects. Thus, our data uncover, for the first time, the origin, development, and basis of the suppressive function of this novel CD11c(+)CD8(+) T-cell subpopulation that has many signature features of Treg.

Publication types

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

MeSH terms

  • Animals
  • CD11c Antigen / metabolism*
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / transplantation
  • Cell Differentiation / immunology
  • Cell Lineage / immunology*
  • Colitis / chemically induced
  • Colitis / immunology
  • Colitis / therapy
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Immune Tolerance / immunology
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Ovalbumin / immunology
  • Peptide Fragments / immunology
  • Protein Serine-Threonine Kinases / genetics
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Spleen / cytology
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / transplantation
  • Transcription Factor CHOP / metabolism
  • Tryptophan / analogs & derivatives
  • Tryptophan / pharmacology
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology

Substances

  • CD11c Antigen
  • Ddit3 protein, mouse
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • OVA-8
  • Peptide Fragments
  • Receptors, Antigen, T-Cell
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Transcription Factor CHOP
  • Tryptophan
  • Ovalbumin
  • Eif2ak4 protein, mouse
  • Protein Serine-Threonine Kinases