Id3 and Id2 act as a dual safety mechanism in regulating the development and population size of innate-like γδ T cells

J Immunol. 2014 Feb 1;192(3):1055-1063. doi: 10.4049/jimmunol.1302694. Epub 2013 Dec 30.

Abstract

The innate-like T cells expressing Vγ1.1 and Vδ6.3 represent a unique T cell lineage sharing features with both the γδ T and the invariant NKT cells. The population size of Vγ1.1(+)Vδ6.3(+) T cells is tightly controlled and usually contributes to a very small proportion of thymic output, but the underlying mechanism remains enigmatic. Deletion of Id3, an inhibitor of E protein transcription factors, can induce an expansion of the Vγ1.1(+)Vδ6.3(+) T cell population. This phenotype is much stronger on the C57BL/6 background than on the 129/sv background. Using quantitative trait linkage analysis, we identified Id2, a homolog of Id3, to be the major modifier of Id3 in limiting Vγ1.1(+)Vδ6.3(+) T cell expansion. The Vγ1.1(+)Vδ6.3(+) phenotype is attributed to an intrinsic weakness of Id2 transcription from Id2 C57BL/6 allele, leading to an overall reduced dosage of Id proteins. However, complete removal of both Id2 and Id3 genes in developing T cells suppressed the expansion of Vγ1.1(+)Vδ6.3(+) T cells because of decreased proliferation and increased cell death. We showed that conditional knockout of Id2 alone is sufficient to promote a moderate expansion of γδ T cells. These regulatory effects of Id2 and Id3 on Vγ1.1(+)Vδ6.3(+) T cells are mediated by titration of E protein activity, because removing one or more copies of E protein genes can restore Vγ1.1(+)Vδ6.3(+) T cell expansion in Id2 and Id3 double conditional knockout mice. Our data indicated that Id2 and Id3 collaboratively control survival and expansion of the γδ lineage through modulating a proper threshold of E proteins.

Publication types

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

MeSH terms

  • Alleles
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / deficiency
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / physiology
  • Cell Lineage
  • Crosses, Genetic
  • Gene Rearrangement, delta-Chain T-Cell Antigen Receptor
  • Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor
  • Inhibitor of Differentiation Protein 2 / deficiency
  • Inhibitor of Differentiation Protein 2 / genetics
  • Inhibitor of Differentiation Protein 2 / physiology*
  • Inhibitor of Differentiation Proteins / deficiency
  • Inhibitor of Differentiation Proteins / genetics
  • Inhibitor of Differentiation Proteins / physiology*
  • Lymphocyte Count
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Antigen, T-Cell, gamma-delta / analysis*
  • Specific Pathogen-Free Organisms
  • T-Lymphocyte Subsets / chemistry
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology*
  • Thymus Gland / cytology
  • Thymus Gland / immunology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Idb2 protein, mouse
  • Inhibitor of Differentiation Protein 2
  • Inhibitor of Differentiation Proteins
  • Receptors, Antigen, T-Cell, gamma-delta
  • Tcf12 protein, mouse
  • Tcf3 protein, mouse
  • Idb3 protein, mouse