Opata, M. M. | bioRxiv Science

bioRxiv2022

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 P. chabaudi protects 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 dividing Ifng+ T cells with BrdU in infected Ifng-reporter mice. A large drop in specific T cell numbers and Ifng+ 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 some Ifng expression. In addition, pre-treatment of chronically-infected animals with neutralizing antibody to IFN-{gamma}, 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 divided Ifng+ T cells, particularly IFN-{gamma}+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-{gamma}+TNF+IL-2- Late Effector Memory and Terminally Differentiated Effector T cells and prolongs immunity.

immunology↗

bioRxiv2022

Functionally competent CD4+ T cells express high levels of T-bet in Plasmodium chabaudi infected young mice

The immune system plays an important role in the elimination of Plasmodium parasites that cause malaria, which affect children the most worldwide. Immunity to malaria, especially in young children is poorly understood due to the absence of a developmentally-equivalent rodent model to study the pathogenesis of disease. We have developed a mouse model using 15-day old mice (pups) of malaria infection in neonatal mice. Using C57BL/6 pups, we determined that P. chabaudi infection decreases the growth rate of young mice compared to controls, and results in 60% mortality, and neurological damage not present in adults, as indicated by a battery of behavioral assays. When all splenic cells were stimulated in vitro stimulation, cells from pups proliferated faster than adult cells, but purified CD4 T cells were slower. Upon infection with Plasmodium parasites, both adult and pup CD4+ T cells were activated and differentiated to an effector T cell (Teff) phenotype; however, pup CD4+ Teff were less differentiated than adult Teff. Pup CD4+ T cells also produced more IL-2 than cells from adult B6 mice, and TNF- was increased in parasite-specific BALB/c pup T cells. Interestingly, there were more pup CD4+T-bethi Teff after infection suggestive of increased Th1 commitment, potentially contributing to cerebral symptoms.

immunology↗