T-bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor β2

Immunity. 2012 Sep 21;37(3):501-10. doi: 10.1016/j.immuni.2012.05.031. Epub 2012 Sep 6.

Abstract

Foxp3(+) regulatory T (Treg) cells limit inflammatory responses and maintain immune homeostasis. Although comprised of several phenotypically and functionally distinct subsets, the differentiation of specialized Treg cell populations within the periphery is poorly characterized. We demonstrate that the development of T-bet(+) Treg cells that potently inhibit T helper 1 (Th1) cell responses was dependent on the transcription factor STAT1 and occurred directly in response to interferon-γ produced by effector T cells. Additionally, delayed induction of the IL-12Rβ2 receptor component after STAT1 activation helped ensure that Treg cells do not readily complete STAT4-dependent Th1 cell development and lose their ability to suppress effector T cell proliferation. Thus, we define a pathway of abortive Th1 cell development that results in the specialization of peripheral Treg cells and demonstrate that impaired expression of a single cytokine receptor helps maintain Treg cell-suppressive function in the context of inflammatory Th1 cell responses.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Flow Cytometry
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Forkhead Transcription Factors / metabolism
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Interferon-gamma / pharmacology
  • Interleukin-12 / pharmacology
  • Interleukin-12 Receptor beta 2 Subunit / genetics
  • Interleukin-12 Receptor beta 2 Subunit / immunology*
  • Interleukin-12 Receptor beta 2 Subunit / metabolism
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Receptors, CXCR3 / genetics
  • Receptors, CXCR3 / immunology
  • Receptors, CXCR3 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / immunology
  • STAT1 Transcription Factor / metabolism
  • STAT4 Transcription Factor / immunology
  • STAT4 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / immunology
  • T-Box Domain Proteins / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Time Factors

Substances

  • Cxcr3 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-12 Receptor beta 2 Subunit
  • Receptors, CXCR3
  • STAT1 Transcription Factor
  • STAT4 Transcription Factor
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Interleukin-12
  • Interferon-gamma