Role of T cell TGF-beta signaling in intestinal cytokine responses and helminthic immune modulation

Eur J Immunol. 2009 Jul;39(7):1870-8. doi: 10.1002/eji.200838956.

Abstract

Colonization with helminthic parasites induces mucosal regulatory cytokines, like IL-10 or TGF-beta, that are important in suppressing colitis. Helminths induce mucosal T cell IL-10 secretion and regulate lamina propria mononuclear cell (LPMC) Th1 cytokine generation in an IL-10-dependent manner in WT mice. Helminths also stimulate mucosal TGF-beta release. As TGF-beta exerts major regulatory effects on T lymphocytes, we investigated the role of T lymphocyte TGF-beta signaling in helminthic modulation of intestinal immunity. T cell TGF-beta signaling is interrupted in TGF-beta receptor II dominant negative (TGF-betaRII DN) mice by T-cell-specific over-expression of a TGF-betaRII DN. We studied LPMC responses in WT and TGF-betaRII DN mice that were uninfected or colonized with the nematode, Heligmosomoides polygyrus. Our results indicate an essential role of T cell TGF-beta signaling in limiting mucosal Th1 and Th2 responses. Furthermore, we demonstrate that helminthic induction of intestinal T cell IL-10 secretion requires intact T cell TGF-beta-signaling pathway. Helminths fail to curtail robust, dysregulated intestinal Th1 cytokine production and chronic colitis in TGF-betaRII DN mice. Thus, T cell TGF-beta signaling is essential for helminthic stimulation of mucosal IL-10 production, helminthic modulation of intestinal IFN-gamma generation and H. polygyrus-mediated suppression of chronic colitis.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Colitis / immunology
  • Colitis / metabolism
  • Colitis / parasitology
  • Cytokines / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Host-Parasite Interactions
  • Interferon-gamma / metabolism
  • Interleukin-10 / metabolism
  • Intestinal Diseases, Parasitic / immunology
  • Intestinal Diseases, Parasitic / metabolism
  • Intestinal Diseases, Parasitic / parasitology
  • Intestine, Small / cytology
  • Intestine, Small / metabolism
  • Intestine, Small / parasitology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Nematospiroides dubius / physiology*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Strongylida Infections / immunology
  • Strongylida Infections / metabolism*
  • Strongylida Infections / parasitology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / metabolism*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*

Substances

  • Cytokines
  • Mutant Proteins
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Interleukin-10
  • Interferon-gamma
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II