Combinatorial Tim-3 and PD-1 activity sustains antigen-specific Th1 cell numbers during blood-stage malaria.
S R., Dookie None., Villegas-Mendez A., Kroeze H., Barrett JR., Draper SJ., Franke-Fayard BM., Janse CJ., MacDonald AS., Couper KN.
AIMS:Co-inhibitory receptors play a major role in controlling the Th1 response during blood-stage malaria. Whilst PD-1 is viewed as the dominant co-inhibitory receptor restricting T cell responses, the roles of other such receptors in coordinating Th1 cell activity during malaria are poorly understood. METHODS AND RESULTS:Here we show that the co-inhibitory receptor Tim-3 is expressed on splenic antigen-specific T-bet+ (Th1) OT-II cells transiently during the early stage of infection with transgenic Plasmodium yoelii NL parasites expressing ovalbumin (P. yoelii NL-OVA). We reveal that co-blockade of Tim-3 and PD-L1 during the acute phase of P. yoelii NL infection did not improve the Th1 cell response but instead led to a specific reduction in the numbers of splenic Th1 OT-II cells. Combined blockade of Tim-3 and PD-L1 did elevate anti-parasite IgG antibody responses. Nevertheless, co-blockade of Tim-3 and PD-L1 did not affect IFN-γ production by OT-II cells and did not influence parasite control during P. yoelii NL-OVA infection. CONCLUSION:Thus, our results show that Tim-3 plays an unexpected combinatorial role with PD-1 in promoting and / or sustaining a Th1 cell response during the early phase of blood-stage P. yoelii NL infection but combined blockade does not dramatically influence anti-parasite immunity.