IL-17RA-signaling modulates CD8+ T cell survival and exhaustion during Trypanosoma cruzi infection

TOSELLO BOARI J; ARAUJO FURLÁN CL; FIOCCA VERNENGO F; RODRIGUEZ C; RAMELLO MC; AMEZCUA VESELY MC; GOROSITO SERRÁN M; NUÑEZ N; RICHER W; PIAGGIO E; MONTES CL; GRUPPI A; ACOSTA RODRIGUEZ EV

Frontiers in Immunology

Frontiers

Lugar: Lausanne; Año: 2018

The IL-17 family contributes to host defense against many intracellular pathogens by mechanisms that are not fully understood. CD8+ T lymphocytes are key elements against intracellular microbes, and their survival and ability to mount cytotoxic responses are orchestrated by several cytokines. Here, we demonstrated that IL-17RA-signaling cytokines sustain pathogen-specific CD8+ T cell immunity. The absence of IL-17RA and IL-17A/F during Trypanosoma cruzi infection resulted in increased tissue parasitism and reduced frequency of parasite-specific CD8+ T cells. Impaired IL-17RA-signaling in vivo increased apoptosis of parasite-specific CD8+ T cells, while in vitro recombinant IL-17 down-regulated the pro-apoptotic protein BAD and promoted the survival of activated CD8+ T cells. Phenotypic, functional, and transcriptomic profiling showed that T. cruzi-specific CD8+ T cells derived from IL-17RA-deficient mice presented features of cell dysfunction. PD-L1 blockade partially restored the magnitude of CD8+ T cell responses and parasite control in these mice. Adoptive transfer experiments established that IL-17RA-signaling is intrinsically required for the proper maintenance of functional effector CD8+ T cells. Altogether, our results identify IL-17RA and IL-17A as critical factors for sustaining CD8+ T cell immunity to T. cruzi.