Transcription factor T-bet regulates intraepithelial lymphocyte functional maturation

Immunity. 2014 Aug 21;41(2):244-56. doi: 10.1016/j.immuni.2014.06.017.

Abstract

The intestinal epithelium harbors large populations of activated and memory lymphocytes, yet these cells do not cause tissue damage in the steady state. We investigated how intestinal T cell effector differentiation is regulated upon migration to the intestinal epithelium. Using gene loss- and gain-of-function strategies, as well as reporter approaches, we showed that cooperation between the transcription factors T-bet and Runx3 resulted in suppression of conventional CD4(+) T helper functions and induction of an intraepithelial lymphocyte (IEL) program that included expression of IEL markers such as CD8αα homodimers. Interferon-γ sensing and T-bet expression by CD4(+) T cells were both required for this program, which was distinct from conventional T helper differentiation but shared by other IEL populations, including TCRαβ(+)CD8αα(+) IELs. We conclude that the gut environment provides cues for IEL maturation through the interplay between T-bet and Runx3, allowing tissue-specific adaptation of mature T lymphocytes.

Publication types

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

MeSH terms

  • Animals
  • CD8 Antigens / biosynthesis
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Colitis / genetics
  • Colitis / immunology
  • Core Binding Factor Alpha 3 Subunit / immunology*
  • DNA-Binding Proteins / immunology
  • Interferon gamma Receptor
  • Interferon-gamma / immunology
  • Interleukins / immunology
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / immunology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Antigen, T-Cell, alpha-beta / biosynthesis
  • Receptors, Cytokine / genetics
  • Receptors, Interferon / genetics
  • Receptors, Interleukin
  • Signal Transduction / immunology
  • T-Box Domain Proteins / biosynthesis
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / immunology*
  • T-Lymphocytes, Helper-Inducer / immunology*
  • Transcription Factors / immunology
  • Tretinoin
  • Up-Regulation

Substances

  • CD8 Antigens
  • CD8 antigen, alpha chain
  • Core Binding Factor Alpha 3 Subunit
  • DNA-Binding Proteins
  • Il27 protein, mouse
  • Il27ra protein, mouse
  • Interleukins
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Cytokine
  • Receptors, Interferon
  • Receptors, Interleukin
  • Runx3 protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Transcription Factors
  • Zbtb7b protein, mouse
  • Tretinoin
  • Interferon-gamma