Effector γδ T Cell Differentiation Relies on Master but Not Auxiliary Th Cell Transcription Factors

J Immunol. 2016 May 1;196(9):3642-52. doi: 10.4049/jimmunol.1501921. Epub 2016 Mar 18.

Abstract

γδ T lymphocytes are programmed into distinct IFN-γ-producing CD27(+) (γδ27(+)) and IL-17-producing CD27(-) (γδ27(-)) subsets that play key roles in protective or pathogenic immune responses. Although the signature cytokines are shared with their αβ Th1 (for γδ27(+)) and Th17 (for γδ27(-)) cell counterparts, we dissect in this study similarities and differences in the transcriptional requirements of murine effector γδ27(+), γδ27(-)CCR6(-), and γδ27(-)CCR6(+) γδ T cell subsets and αβ T cells. We found they share dependence on the master transcription factors T-bet and RORγt for IFN-γ and IL-17 production, respectively. However, Eomes is fully dispensable for IFN-γ production by γδ T cells. Furthermore, the Th17 cell auxiliary transcription factors RORα and BATF are not required for IL-17 production by γδ27(-) cell subsets. We also show that γδ27(-) (but not γδ27(+)) cells become polyfunctional upon IL-1β plus IL-23 stimulation, cosecreting IL-17A, IL-17F, IL-22, GM-CSF, and IFN-γ. Collectively, our in vitro and in vivo data firmly establish the molecular segregation between γδ27(+) and γδ27(-) T cell subsets and provide novel insight on the nonoverlapping transcriptional networks that control the differentiation of effector γδ versus αβ T cell subsets.

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Cell Differentiation
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism
  • Interleukin-17 / biosynthesis
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Interleukin-1beta / immunology
  • Interleukin-23 / immunology
  • Interleukins / metabolism
  • Lymphocyte Activation
  • Mice
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Receptors, Antigen, T-Cell, gamma-delta / analysis
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism*
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / physiology
  • Th17 Cells / immunology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Basic-Leucine Zipper Transcription Factors
  • Batf protein, mouse
  • Interleukin-17
  • Interleukin-1beta
  • Interleukin-23
  • Interleukins
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Receptors, Antigen, T-Cell, gamma-delta
  • Rorc protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Transcription Factors
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • interleukin-22