Innate iNKT Cells Shape Organ-Specific Pathogenesis in Plasmodium Infection - Abstract Cerebral malaria is a severe complication of Plasmodium infection that can result in death. The main pathogenic effector cells are CD8 T cells that produce IFN-g; however, it is known that invariant natural killer T (iNKT) cells are needed in the Plasmodium berghei ANKA experimental cerebral malaria (ECM) model. The overarching hypothesis of this proposal is that iNKT cells provide the initial cytokines that drive pathogenic IFN-g producing anti-Plasmodium CD8 T cells. iNKT cells are a unique group of innate T cells that recognize glycolipid antigens and have the ability to produce cytokines rapidly following TCR stimulation. Although iNKT cells differ from conventional T cells in the types of antigens they recognize, iNKT cells are similar in that they produce effector cytokines such as IFN-g, IL-4, and IL-17 that can be characterized as iNKT1, iNKT2, and iNKT17 subsets respectively. These cells play important roles in the control of cancer, infections, and autoimmune diseases as they are often the initial source of T cell effector cytokines triggered prior to adaptive immune cells. Published work from the Evavold lab, and others, has demonstrated that conventional T cells become activated through TCRs that are a mechanosensor in which the affinity and bond lifetime under force determines the effector functions. Unlike the adaptive T cell response which is more nuanced, innate T cells (iNKT, gd, MAIT, or ILCs) respond to triggering antigen in a binary on/off manner. Our R21 proposal will be the first to examine the role of 2D affinity and applied force to the TCR in the cytokine response of iNKT cells and will define how these features shape development of CD8 T cell-driven ECM. The central hypothesis of our grant revolves around the idea that, like conventional ab T cells, the TCR for iNKT can be classified as a mechanosensor that integrates differences in 2D affinity and bond lifetimes under force of the presented glycolipid antigens resulting in discrete cytokine production and phenotype. Based on preliminary data, the working hypothesis of this grant is that bond lifetime under force determines effector phenotype in iNKT cells and that manipulation of iNKT cell activation in the periphery can be utilized as a novel adjunctive therapy for CD8-mediated organ-specific pathologies in malaria. We predict that conserved ligands with a lower affinity and shorter bond lifetime in P. berghei ANKA infection will favor iNKT2 cell responses and provide protection from neurological manifestations of Plasmodium infection in the ECM model. Our working hypothesis will be tested under 2 specific aims: Aim 1. Define the strength of signal exerted by the TCR of iNKT cell subsets in both naïve mice and those with P. berghei ANKA infection Aim 2. Prohibit the expansion and trafficking of pathogenic IFN-g secreting Plasmodium-reactive CD8 T cells through administration of chemotherapeutic iNKT2-inducing lipid antigens
