The role of CD4+ T cell help and the co-stimulatory molecule CD40 in protective immunity against liver stage Plasmodium infection

Abstract

Live, attenuated <italic>Plasmodium</italic> vaccines against liver stage infection have shown great promise in the mouse model and are being optimized in preliminary human clinical trials. While CD8+ T cells play a key role in mediating immunity conferred by attenuated parasites, it is unclear what signals CD8+ T cells receive from antigen-presenting cells (APC) or CD4+ T helper cells during priming that induce an effective memory response. The late-arresting vaccine strain <italic>fabb/f-</italic> induces powerful, CD4+ T cell-dependent, sterilizing immunity and can be used to determine what mechanisms must be triggered during immunization to generate a protective and long-lasting response that prevents malaria. As a route of CD4+ T cell help, the co-stimulatory molecule CD40 enhances immunity through several distinct roles in T cell activation memory formation. CD40 was critical for the full maturation of liver dendritic cells, clonal expansion of CD8+ T cells in the liver, and protective immunity immunization with the <italic>P. yoelii fabb/f-</italic> genetically attenuated parasite (GAP). We evaluated the contributions to CD8+ T cell immunity of CD40 expressed on APC as compared to CD40 expressed on CD8+ T cells. Most of the effects of CD40 could be accounted for by expression in the T cells' environment, but CD40 on the CD8+ T cells themselves had a distinctive role in limiting effector cell differentiation and controlling the expression of exhaustion-associated markers. Thus CD40 on APC drives clonal-expansion of effector cells, but unopposed this signal discriminates against the formation of memory. CD40 expressed on the CD8+ T cells themselves balances this, allowing the formation of long-lived memory cells. We conclude that protective immunity conferred by late-arresting parasite vaccines relies heavily on CD4+ T cell help, APC licensing and strong co-stimulatory signals via CD40 to prime both effector CD8+ T cells and long-lived memory T cells.