IL-17 A and F sustain CD8+ T cell response to T cruzi by modulating survival, differentiation and exhaustion partially Through CD8+ T cell intrinsic IL-17RA signaling

TOSELLO BOARI J; ARAUJO FURLÁN CINTIA;; FIOCCA VEMENGO F; RAMELLO MC; GOROSITO SERRAN M; MONTES CL; GRUPPI A; ACOSTA RODRIGUEZ EV

Congreso; LIX Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica. LXII Reunión Anual de la Sociedad Argentina de Inmunologia; 2014

The IL17 family contributes to host defense against intracellular microbes by inducing inflammation and immune cell recruitment. We described a novel mechanism by which IL17RA is critically involved in the induction of CD8+ T cell (CTL) responses. We demonstrated that compared to WT mice, IL17RA KO (KO) mice infected with T. cruzi (Tc) developed a reduced frequency of Tc-specific CTL. Here, we investigated whether the IL17RA requirement for robust CTL responses is CTL intrinsic and which particular IL17RA-signaling cytokine is involved. We determined that IL17RA is constitutively present in CTL and induced upon Tc infection. Next, we performed adoptive transfer assays to determine if IL17RA expression on the CTL itself provided an advantage to survive and respond to Tc. First, we transferred CTL from CD45.1 WT mice into CD45.2 WT and KO host and analyzed upon infection, the contribution of the injected cells to the CTL response. After 20 days post infection (dpi), the contribution of injected CD45.1 CTL to Tc-specific CTL pools was higher in KO than in WT hosts (blood p=0.003; spleen p=0.011). Convincingly, we transferred equal numbers of CTL from CD45.1 WT and CD45.2 KO mice into CD45.1/2 hosts. After 20dpi, injected KO CTL were significantly outcompeted by their WT counterparts (blood p=0.016; spleen p=0.014). To elucidate the IL17 cytokine critical for CTL responses, we evaluated how lack of IL17A/F affected the course of Tc infection. Infected IL17A/F KO mice showed the same phenotype than infected KO mice (i.e. increased tissue parasitism, reduced total and Tc-specific CTL and exhausted CTL phenotype). Finally, we determined that purified naive CTL upregulated IL17RA expression upon TCR engagement and become responsive to rIL17A that diminished the% of AnnexinV+ cells (p