IL-17A and IL-2-expanded regulatory T cells cooperate to inhibit Th1-mediated rejection of MHC II disparate skin grafts

PLoS One. 2013 Oct 11;8(10):e76040. doi: 10.1371/journal.pone.0076040. eCollection 2013.

Abstract

Several evidences suggest that regulatory T cells (Treg) promote Th17 differentiation. Based on this hypothesis, we tested the effect of IL-17A neutralization in a model of skin transplantation in which long-term graft survival depends on a strong in vivo Treg expansion induced by transient exogenous IL-2 administration. As expected, IL-2 supplementation prevented rejection of MHC class II disparate skin allografts but, surprisingly, not in IL-17A-deficient recipients. We attested that IL-17A was not required for IL-2-mediated Treg expansion, intragraft recruitment or suppressive capacities. Instead, IL-17A prevented allograft rejection by inhibiting Th1 alloreactivity independently of Tregs. Indeed, T-bet expression of naive alloreactive CD4+ T cells and the subsequent Th1 immune response was significantly enhanced in IL-17A deficient mice. Our results illustrate for the first time a protective role of IL-17A in CD4+-mediated allograft rejection process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Communication
  • Cell Proliferation
  • Gene Expression
  • Graft Rejection / immunology
  • Graft Rejection / prevention & control*
  • Graft Survival / immunology*
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology
  • Interleukin-17 / deficiency
  • Interleukin-17 / immunology*
  • Interleukin-2 / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Skin Transplantation*
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • T-bet Transcription Factor
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Th17 Cells / immunology
  • Th17 Cells / metabolism

Substances

  • Histocompatibility Antigens Class II
  • Interleukin-17
  • Interleukin-2
  • T-Box Domain Proteins
  • T-bet Transcription Factor

Grants and funding

This work was funded by the Roche Organ Transplantation Research Foundation (ROTRF) http://www.rotrf.org/. The Institute for Medical Immunology is funded by research grants of the Walloon Region (www.wallonie.be), the FNRS-Belgium and GlaxoSmithKline Biologicals (www.gsk.com). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.