The antigen-specific CD4 host response to Plasmodium yoelii 17XL infection after protective MSP-8 immunization alters multifunctional cytokine profiles (45.13)

Abstract

Abstract Multifunctional CD4 T cells, which produce combinations of interferon gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and IL-2, have been shown to be immune correlates of protection after vaccination in a mouse model of L. major and for some models of M. tuberculosis. In this study, we have used multi-parameter flow cytometry to study a merozoite-surface protein-based (MSP-8) vaccine model against lethal murine Plasmodium yoelii (Py) infection, which we have shown to be dependent on IFN-γ and which also requires an active immune response during challenge infection for protection and survival. Our data supports previous studies, which have found that the patterns of multifunctional responses are established after the first immunization but the frequencies of CD4 responders and the amount of IFN-γ produced per multifunctional cell increase with subsequent immunizations. We further show that antigen-specific memory CD4 cells in the lymph nodes are functionally distinct from those in the spleen and liver before and after Py challenge. Also, the nonlymphoid-tissue (liver) responses occur at the greatest frequency and show the greatest plasticity in cytokine profile during infection. We conclude that this protective immunization induces multifunctional 3+ antigen-specific CD4 T cells (10-25% of MSP-8 specific CD4s) but that the host response to lethal malaria infection triggers a shift in multifunctionality towards more IFN-γ production, especially in non-lymphoid tissue. Funding Sources: J. Burns (NIH #AI35661), C. Long (Intramural Program of NIH-NIAID)