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 withPlasmodium 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-levelP. chabaudiprotects the host from re-infection at two months post-infection, 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 labelling dividingIfng+T cells with BrdU in infectedIfng-reporter mice. A large drop in specific T cell numbers andIfng+cells upon clearance of parasite suggest a mechanism for decay of protection. Although protection decays, CD4 Tmem persist, including a highly-differentiated CD27-Effector Memory (Tem) subset that maintains someIfngexpression. In addition, pre-treatment of chronically-infected animals with neutralizing antibody to IFN-γ, or clodronate liposomes before re-infection decrease premonition supporting a role for Th1-type immunity to re-infection. A pulse/chase experiment comparing chronically infected to treated animals showed that recently dividedIfng+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 survival and multi-functional Teff but promotes IFN-γ+TNF+IL-2-Late Effector Memory and Terminally Differentiated Effector T cells and prolongs immunity.