Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells

J Exp Med. 2008 Jul 7;205(7):1543-50. doi: 10.1084/jem.20080321.

Abstract

The cytokines controlling the development of human interleukin (IL) 17--producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17--producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) beta, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17--producing T cells. These data suggest that IL-12Rbeta1- and STAT-3--dependent signals play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cytokines / genetics
  • Cytokines / immunology
  • Female
  • Genetic Diseases, Inborn / genetics
  • Genetic Diseases, Inborn / immunology*
  • Humans
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Interleukin-1 Receptor-Associated Kinases / immunology
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology*
  • Male
  • Mutation
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / immunology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / immunology
  • Quantitative Trait Loci / immunology
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Interleukin-12 / genetics
  • Receptors, Interleukin-12 / immunology*
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / immunology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • T-Lymphocytes, Helper-Inducer / immunology*

Substances

  • Cytokines
  • IL12RB1 protein, human
  • Interleukin-17
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • Receptors, Interleukin-12
  • Receptors, Transforming Growth Factor beta
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • IRAK4 protein, human
  • Interleukin-1 Receptor-Associated Kinases
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • TGFBR1 protein, human