Characterization of antigen-specific CD8 T cell responses in experimental cerebral malaria

Malaria remains a major global health concern, infecting more than 200 million individuals and resulting in almost a half a million deaths per year. Most malaria-associated deaths are caused by cerebral malaria (CM). Due to ethical limitations of human experimentation, an experimental cerebral malaria (ECM) model is used to further our understanding of the pathogenesis of CM. C57BL/6 mice are susceptible to ECM upon Plasmodium berghei ANKA live sporozoite (spz) or infected RBC (iRBC) infection. CD8 T cells are required for ECM symptoms as depletion of CD8 T cells inhibits disease. Despite the known role of CD8 T cells in the pathogenesis of ECM, the kinetics, phenotype and function of antigen-specific response have not been described. Here, we characterize the antigen-specific CD8 T cell phenotype after spz or iRBC infection and correlate with parasitemia levels and development of ECM. Using surrogate activation markers to identify antigen-specific CD8 T cells, the frequency of CXCR3 expressing activated CD8 T cells decreased initially and subsequently increased during onset of ECM symptoms. Higher parasitemia levels and frequency of activated CD8 T cells correlated with ECM development in both spz and iRBC infection models. Based on these data, we hypothesize that ECM develops in a goldilocks-principle manner. If a specific threshold of parasitemia and activated CD8 T cells are reached at the same time, ECM develops, but should the CD8 T cell response occur too early or late, ECM does not develop and mice will eventually succumb to hyperparasitemia and severe anemia.