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.
Highlights
Myd88-deficient animals are highly susceptible to infection by multiple pathogens, including T. cruzi, and exhibit diminished Th1 differentiation, which has been attributed to defective IL-12 production by APCs, as a consequence of poor TLR signaling (Campos et al, 2004; Fremond et al, 2004; Scanga et al, 2002; Seki et al, 2002; Muraille et al, 2003)
Including residual WT recipient cells (CD45.1+CD45.2+), the mixed BM chimeras have more than 50% of WT DC in their spleen (Figure 1—figure supplement 1B) able to be fully activated by TLR pathways during infection with T. cruzi
Since MyD88 is an essential adaptor molecule downstream of most TLRs, and of IL-1 and IL-18 pathways, we investigated whether the lack of IL-1R or IL-18R would by itself reproduce the effects observed in Myd88À/À T cells
Summary
Myd88-deficient animals are highly susceptible to infection by multiple pathogens, including T. cruzi, and exhibit diminished Th1 differentiation, which has been attributed to defective IL-12 production by APCs, as a consequence of poor TLR signaling (Campos et al, 2004; Fremond et al, 2004; Scanga et al, 2002; Seki et al, 2002; Muraille et al, 2003). Few studies to date have directly addressed the relevance of T cell-intrinsic MyD88 signaling pathways for the establishment of in vivo cognate Th1 responses in the context of infection (Frazer et al, 2013; LaRosa et al, 2008; Raetz et al, 2013; Zhou et al, 2009). No consensus exists about the relative contribution of different receptors upstream MyD88 necessary for sustaining a robust Th1 response and contributing to CD4+ T cell memory formation in a model of infection
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