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

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.

NLRP3 Inflammasome Participates in Host Response to Neospora caninum Infection

“…In T. gondii -infected Il18 −/− and Il18r −/− mice, parasite replication was increased, and murine survival was impaired ( 20 ). Il18r1 −/− mice were highly susceptible to T. cruzi infection and had high parasite load ( 58 ). Leishmania infection caused higher parasite burden and significantly increased lesion size in Il18 −/− mice ( 59 ).…”

Bystander T Cells: A Balancing Act of Friends and Foes

“…Thus, the induction of bystander T cell activation is heavily dependent on the cytokine milieu, for instance during infection, and is often confined to the site of pathogen localization [38, 43, 87-90]. Indeed, IL-12, IL-15, and IL-18 appear to be important regulators of bystander T cell responses, and are secreted by mononuclear cells in response to viral and bacterial infections in mice and humans [38, 43, 91, 92].…”

“…CD8 + T cells from patients infected with Hepatitis A virus (HAV) can be activated in an IL-15-dependent and TCR-independent manner, contributing to liver injury, given that CD8 + T cells that were non-HAV-specific could be detected in patient liver samples and which could exert cytotoxicity [44]. In the case of IL-18, this cytokine can stimulate the production of IFNγ by memory CD8 + T cells during bacterial and parasitic infections [38, 92], and has been shown to synergize with IL-12 for optimal IFNγ production by CD4 + Th1 cells and CD8 + T cells during viral infections in humans and mice [95, 96]. This suggests a complex landscape of cytokine interactions that may modify T cell function during infections, and which based on a deeper understanding, may provide insight into potential cytokine-based treatments.…”

Toxocara canis Differentially Affects Hepatic MicroRNA Expression in Beagle Dogs at Different Stages of Infection

“…Additionally, cfa-miR-133c was predicted to regulate the IL18R1 gene. Previous research found that IL-18R/MyD88 plays a crucial role in the development of a robust Th1 response during Trypanosoma cruzi infection (39). Therefore, the abnormal expression of cfa-miR-133c seems to be a potential candidate for further study of the role of cfa-miR-133c in promoting a protective Th1 immune response to T. canis infection.…”