Using Two Phases of the CD4 T cell Response to Blood-Stage Murine Malaria to understand Regulation of Systemic Immunity and Placental Pathology in P. falciparum infection

P. falciparum infection and malaria remain a risk for millions of children and pregnant women. Here, we seek to integrate knowledge of mouse and human T helper cell (Th) responses to blood-stage Plasmodium infection to understand their contribution to protection and pathology. Although there is no complete Th subset differentiation, the adaptive response occurs in two phases in non-lethal rodent Plasmodium infection, coordinated by Th cells. In short, cellular immune responses limit the peak of parasitemia during the first phase; in the second phase, humoral immunity from T cell dependent germinal centers is critical for complete clearance of rapidly changing parasite. A strong IFN-γ response kills parasite, but an excess of TNF compared to regulatory cytokines (IL-10, TGF-β) can cause immunopathology. This common pathway for pathology is associated with anemia, cerebral malaria and placental malaria. These two phases can be used to both understand how the host responds to rapidly growing parasite, and how it attempts to control immunopathology and variation. This dual nature of T cell immunity to Plasmodium is discussed, with particular reference to the protective nature of the continuous generation of effector T cells, and the unique contribution of effector memory T cells.