IL-17RA-signaling sustains immunity to Trypanosoma cruzi by modulating CD8+ T cell survival, differentiation and exhaustion

TOSELLO BOARI J; ARAUJO FURLLÁN C; FIOCCA F; RAMELLO MC; AMEZCUA VESELY C; NUÑEZ N; CAGNARD N; PIAGGIO E; MONTES CL; GRUPPI A; ACOSTA RODRIGUEZ EV

Congreso; Keystone Symposia: T Cells: Regulation and Effector Function (D3); 2015

CD8+ T lymphocytes (CTL) are key elements in the defense against intracellular pathogens and cytokines are critical signals shaping protective CTL responses during infections. The IL-17 family has been recently shown to contribute to host defense against many intracellular pathogens but the protective mechanisms remains not fully understood. Here, we describe a new effector mechanism by which IL-17RA-signaling cytokines are critically involved in sustaining pathogen-specific CTL responses. IL-17RA knockout mice infected with the protozoan parasite Trypanosoma cruzi developed a reduced frequency of parasite-specific CTL that correlated with decreased antigen-specific cytotoxicity in vivo and increased tissue parasitism. Adoptive transfer experiments established that CTL intrinsic IL-17RA-signaling is required for the maintenance of effector CTL during T. cruzi infection. Absence of IL-17RA-signaling did not affect expansion but reduced survival of parasite-specific CTL. Phenotypic, functional and genomic profiling determined that T. cruzi-specific CTL arising in the absence of IL-17RA-signaling presented an aberrant phenotype resembling memory cells with signs of high activation and exhaustion. Altogether, our results identify IL-17RA-signaling cytokines as critical factors for sustaining robust CTL immunity to T. cruzi and, likely, to other intracellular microbes.