Effects of Low-Level Persistent Infection on Maintenance of Immunity by CD4 T Cell Subsets and Th1 Cytokines.

CD4 T cells are required, along with antibodies, for complete protection from blood-stage infection with Plasmodium spp., which cause malaria. Without continuous exposure, as on emigration of people from endemic areas, protection from malaria decays. As in other persistent infections, low-level Plasmodium chabaudi infection protects the host from reinfection at 2 months postinfection, a phenomenon termed premunition. Premunition is correlated with T cell responses, rather than antibody levels. We previously showed that while both effector T cells (Teff) and memory T cells (Tmem) are present after infection, Teff protect better than Tmem. Here, we studied T cell kinetics post-infection by labeling dividing T cells with 5-bromo-2'-deoxyuridine (BrdU) in infected reporter mice. Large drops in specific T cell numbers and cells upon clearance of parasites suggest a mechanism for decay of protection. Although protection decays, CD4 Tmem persist, including a highly differentiated CD27 effector memory (Tem) subset that maintains some expression. In addition, pretreatment of chronically infected animals with neutralizing antibody to interferon gamma (IFN-γ) or with clodronate liposomes before reinfection decreases premunition, supporting a role for Th1-type immunity to reinfection. A pulse-chase experiment comparing chronically infected to treated animals showed that recently divided T cells, particularly IFN-γ TNF IL-2 T cells, are promoted by persistent infection. These data suggest that low-level persistent infection reduces CD4 Tmem and multifunctional Teff survival, but promotes IFN-γ TNF IL-2 T cells and terminally differentiated effector T cells, and prolongs immunity.