Co-inhibitory and co-stimulatory crosstalk regulates helper T cell differentiation and humoral immunity during Plasmodium infection (MPF5P.742)

Abstract Pathogen-specific T cells are subject to co-stimulatory and co-inhibitory signals, the balance of which promotes pathogen control while limiting immunopathology. During blood-stage Plasmodium infection, parasite-specific CD4 T cells express PD-1 and LAG-3 co-inhibitory receptors that coordinately limit CD4 T cell function. Blockade of PD-1/LAG-3 co-inhibitory signaling during chronic Plasmodium infection enhances CD4 T cell function and parasite control. In contrast to co-inhibitory receptors, the role of T cell co-stimulatory receptors during established Plasmodium infection has not been investigated. Here we show that CD4 T cells exhibit sustained expression of the co-stimulatory receptor OX40 during both human and experimental malaria. We hypothesized that co-stimulatory signaling can functionally counteract co-inhibitory circuits to maintain protective Plasmodium-specific CD4 T responses. In support of this, therapeutically activating OX40 during established experimental malaria enhances CD4 T cell activity, humoral immunity and parasite clearance. Our data also show that the effects of OX40 signaling are modified following simultaneous PD-1 blockade, which markedly impairs parasite-specific T follicular helper cell responses in an IFN-g-dependent manner. Collectively, our results identify that OX40 can be targeted to limit malaria parasite replication and reveal a previously unrecognized role of IFN-g as a negative regulator of Plasmodium-specific humoral immunity.