c-Rel Promotes Type 1 and Type 17 Immune Responses During Leishmania Major Infection

Eur J Immunol. 2011 May;41(5):1388-98. doi: 10.1002/eji.201041056. Epub 2011 Apr 11.

Abstract

Recent studies demonstrated the crucial role of c-Rel in directing Treg lineage commitment and its involvement in T helper 1 (Th1) cell-mediated autoimmune inflammation. We thus wondered whether these opposite functions of c-Rel influence the course of antiparasitic immune responses against Leishmania major, an accepted model for the impact of T-cell subsets on disease outcome. Here we show that c-Rel-deficient (rel(-/-) ) mice infected with L. major displayed dramatically exacerbated leishmaniasis and enhanced parasite burdens. In contrast to WT mice, IFN-γ and IL-17 production in response to L. major antigens was severely impaired in rel(-/-) mice. Reconstitution of Rag1(-/-) T-cell deficient mice with rel(-/-) CD4(+) T cells followed by L. major infection demonstrated that c-Rel-deficient T cells mount normal Th1 responses and are able to contain the infection. Similarly, Th1 differentiation of naïve CD4(+) cells in vitro was normal. Notably, a selective defect in IL-12 and IL-23 production was observed in rel(-/-) DCs compared with their WT counterparts. In conclusion, our data suggest that the expression of c-Rel in myeloid cells is essential for clearance of L. major and that this c-Rel-mediated effect is dominant over the lack of Tregs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Homeodomain Proteins / genetics
  • Interferon-gamma / biosynthesis
  • Interleukin-12 / deficiency
  • Interleukin-12 / genetics
  • Interleukin-17 / biosynthesis
  • Interleukin-23 / genetics
  • Leishmania major / immunology*
  • Leishmania major / physiology
  • Leishmaniasis, Cutaneous / immunology*
  • Leishmaniasis, Cutaneous / parasitology
  • Macrophages / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proto-Oncogene Proteins c-rel / deficiency
  • Proto-Oncogene Proteins c-rel / genetics
  • Proto-Oncogene Proteins c-rel / metabolism*
  • T-Lymphocytes, Regulatory / immunology
  • Th1 Cells / immunology*
  • Th17 Cells / immunology*

Substances

  • Homeodomain Proteins
  • Interleukin-17
  • Interleukin-23
  • Proto-Oncogene Proteins c-rel
  • RAG-1 protein
  • Interleukin-12
  • Interferon-gamma