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

J TOSELLO; C ARAUJO; F FIOCCA; M RAMELLO; M AMEZCUA; M GOROSITO; N NUÑEZ; N CAGNARD; E PIAGGIO; C MONTES; A GRUPPI; E ACOSTA

Lofoten

Workshop; Workshop: Genetic control of immune cell activation. Implication for autoimmune Disease; 2015

CD8+ T cells (CTL) play particularly important roles in adaptive immune host defense against intracellular pathogens, including Trypanosoma cruzi, the causative agent of human Chagas? disease. We described an effector mechanism by which IL17RA signaling cytokines are critically involved in the development of CD8 specific responses. IL17RA-KO mice infected with T. cruzi showed a reduced frequency of TSKB20-specific CTL when it was compared with WT mice. Furthermore, totals and specifics CTL expressed a phenotype resembling memory cells with signs of high activation and exhaustion, which resulted in decreased antigen-specific cytotoxicity in vivo and increased tissue parasitism. Conclusivelyadoptive 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. At this time to elucidate which of cytokine of IL17 family was involved, we evaluated the CTL response in infected IL17A/F-KO and WT mice. IL17A/F-KO mice showed increased tissue parasitism in blood that correlated with reduced numbers of spleen specific CTL and an aberrant phenotype like IL17RA-KO. Altogether, our results identify IL-17RA and IL-17A/IL-17F as critical factors for sustaining robust CD8+ T cell immunity during T. cruzi infection and, likely, in the context of others infections caused by intracellular microbes, tumor processes or autoimmune diseases.