T-Cell Intrinsic IL-18R/MyD88 Signaling Controls the Generation of Cytotoxic CD4 + T Cell Response

Cytotoxic CD4+ T cells (CD4CTLs) have been described in humans and mice, but the mechanism leading to their differentiation is not fully understood and remains a fundamental question. Here, we investigate the generation of CD4CTLs during infection with Trypanosoma cruzi, an important human pathogen. We demonstrate the critical role of T-cell intrinsic IL-18R/MyD88 signaling for the development of CD4CTLs in infected mixed-BM chimeras: WT but not Myd88-/- CD4+ T cells display the CD4CTL gene signature and IL-18R deficiency phenocopied the absence of MyD88. Moreover, IL-12p40, but not IFN-γ, is required for CD4CTL differentiation. Functionally, degranulating CD4CTLs are massively present in the spleen and myocardium of infected mice, exhibit FasL-dependent antigen-specific cytotoxicity against macrophages in vitro, eliminate target cells in vivo and express important immunoregulatory molecules. The present work discloses a mechanistic framework required for the induction of a robust CD4CTL response to infection with an intracellular parasite.