Crucial role for T cell-intrinsic IL-18R-MyD88 signaling in cognate immune response to intracellular parasite infection

Elife. 2017 Sep 12;6:e30883. doi: 10.7554/eLife.30883.

Abstract

MyD88 is the main adaptor molecule for TLR and IL-1R family members. Here, we demonstrated that T-cell intrinsic MyD88 signaling is required for proliferation, protection from apoptosis and expression of activation/memory genes during infection with the intracellular parasite Trypanosoma cruzi, as evidenced by transcriptome and cytometry analyses in mixed bone-marrow (BM) chimeras. The lack of direct IL-18R signaling in T cells, but not of IL-1R, phenocopied the absence of the MyD88 pathway, indicating that IL-18R is a critical MyD88-upstream pathway involved in the establishment of the Th1 response against an in vivo infection, a presently controvert subject. Accordingly, Il18r1-/- mice display lower levels of Th1 cells and are highly susceptible to infection, but can be rescued from mortality by the adoptive transfer of WT CD4+ T cells. Our findings establish the T-cell intrinsic IL-18R/MyD88 pathway as a crucial element for induction of cognate Th1 responses against an important human pathogen.

Keywords: MyD88; Th1; Trypanosoma cruzi; immunology; mouse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Chagas Disease / immunology*
  • Chagas Disease / therapy
  • Disease Models, Animal
  • Flow Cytometry
  • Gene Expression Profiling
  • Interleukin-18 Receptor alpha Subunit / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / metabolism*
  • Signal Transduction*
  • Survival Analysis
  • Th1 Cells / immunology*
  • Th1 Cells / parasitology*
  • Trypanosoma cruzi / immunology*

Substances

  • Il18r1 protein, mouse
  • Interleukin-18 Receptor alpha Subunit
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.