IL-17RA REGULATES THE MAGNITUDE OF CD8+ T CELL RESPONSE TO T. CRUZI BY MODULATING APOPTOSIS, CELL EXHAUSTION AND MEMORY DIFFERENTIATION

TOSELLO BOARI, JIMENA; FIOCCA VERNENGO, FACUNDO; RAMELLO, MARIA CECILIA; AMEZCUA VESELY, MARIA CAROLINA; ARAUJO FURLAN, CINTIA; MONTES, CAROLINA LUCIA; GRUPPI, ADRIANA; ACOSTA RODRIGUEZ E V

Los Cocos

Jornada; LXI Reunión Anual de la sociedad argentina de Inmunología .; 2013

Sociedad Argentina de Inmunologia

IL-17RA-signaling promotes host survival during T. cruzi infection by controlling exacerbated inflammation, but additional protective mechanisms would be involved. As development of robust CD8+ T cell (CTL) immunity is a key element for host resistance to T. cruzi, we aimed at evaluating if IL17RA is involved in the generation of protective CTL responses. To address this, we evaluated the magnitude and quality of the CTL response in infected IL17RA knockout (INF-KO) mice in comparison to WT controls. INF-KO mice showed increased tissue parasitism in spleen and liver that correlated with reduced numbers of CTL specific for the inmunodominant T. cruzi epitope TSKB20 (TSKB20-specific CTL, spleen, d20pi: 1,7±1,4x106 in KO vs 5,5±2,3x106 in WT mice, p<0.001). Accordingly, CTL from INF-KO mice showed reduced effector function determined by in vitro and in vivo assays. BrDU incorporation experiments ruled out the requirement of IL17RA for normal CTL expansion but ex-vivo annexin V staining showed that IL17RA is required for proper survival of specific CTL (% AnnexinV+TSKB20-specific CTL, d20pi: 59±4 in KO vs 42±7 in WT mice, p=0.0015). Of note, total and TSKB20-specific CTL from INF-KO mice showed increased expression of Fas, PD-1, KLRG-1 and CD11c, indicating that CTL activated in absence of IL17RA had a phenotype of apoptosis-prone/exhausted terminal effector cells. Indeed, adoptive transfer experiments demonstrated that CTL from INF-KO mice showed poorer capability to reconstitute lymphopenic hosts and to protect immunodeficient mice against rechallenge. Additional adoptive transfer experiments also showed that IL17RA-signaling intrinsic to the CD8+ T cell is required for proper CTL response. Our results indicate that during T. cruzi infection IL17RA signaling is not required for the expansion of CTL but rather to prevent a premature cell death and to support robust and long-lived protective CD8+ T cell responses likely by modulating effector versus memory cell fate