Protection by and maintenance of CD4 effector memory and effector T cell subsets in persistent malaria infection

Abstract

Protection at the peak of Plasmodium chabaudi blood-stage malaria infection is provided by CD4 T cells. We have shown that an increase in Th1 cells also correlates with protection during the persistent phase of malaria; however, it is unclear how these T cells are maintained. Persistent malaria infection promotes protection and generates both effector T cells (Teff), and effector memory T cells (Tem). We have previously defined new CD4 Teff (IL-7Rα-) subsets from Early (TeffEarly, CD62LhiCD27+) to Late (TeffLate, CD62LloCD27-) activation states. Here, we tested these effector and memory T cell subsets for their ability to survive and protect in vivo. We found that both polyclonal and P. chabaudi Merozoite Surface Protein-1 (MSP-1)-specific B5 TCR transgenic Tem survive better than Teff. Surprisingly, as Tem are associated with antigen persistence, Tem survive well even after clearance of infection. As previously shown during T cell contraction, TeffEarly, which can generate Tem, also survive better than other Teff subsets in uninfected recipients. Two other Tem survival mechanisms identified here are that low-level chronic infection promotes Tem both by driving their proliferation, and by programming production of Tem from Tcm. Protective CD4 T cell phenotypes have not been precisely determined in malaria, or other persistent infections. Therefore, we tested purified memory (Tmem) and Teff subsets in protection from peak pathology and parasitemia in immunocompromised recipient mice. Strikingly, among Tmem (IL-7Rαhi) subsets, only TemLate (CD62LloCD27-) reduced peak parasitemia (19%), though the dominant memory subset is TemEarly, which is not protective. In contrast, all Teff subsets reduced peak parasitemia by more than half, and mature Teff can generate Tem, though less. In summary, we have elucidated four mechanisms of Tem maintenance, and identified two long-lived T cell subsets (TemLate, TeffEarly) that may represent correlates of protection or a target for longer-lived vaccine-induced protection against malaria blood-stages.

Hepatic Inflammation Confers Protective Immunity Against Liver Stages of Malaria Parasite

“…In our model, it was striking to observe that 70 days after the last SPZ challenge, in contrast to radiationattenuated SPZ immunization protocol, challenged MDR2 −/− mice only maintained a substantially elevated absolute numbers of CD4 Tcm cells, but not Tcm CD8 cells nor CD8 and CD4 Tem cells. This is also in contrast to P. chabaudiinfected mice that continue to generate Tem long time after parasite clearance (62). The discrepancies between these findings are very likely due to the particular genotype of mice used in our study and also to the particular inflammatory events taking place in Mdr2 −/− mice.…”

Modulation of adaptive and innate immune responses by myeloid cells during malaria

“…It is generally accepted in literature that TCM are long-lived with high differentiation potential and TEM are superior at effector functions, but at the expense of longevity, hence one of the factors contributing to temporal decay of malaria protective immunity. [224,386,387]. This proposed model of bi-linear differentiation was supported by numerous other studies in viral and bacterial infection models in both humans and mice, and highlights heterogeneity and plasticity of effector and memory T-cell differentiation and generation [388].…”

“…However, Opata et al also reported that early TEFFE parallel differentiation into TCM  TEM was already programmed to occur during acute PccAS infection, in concordance with early TEFFE  late TEFFL differentiation by peak parasitemia and beyond [115,[386][387][388]. It is generally accepted in literature that TCM are long-lived with high differentiation potential and TEM are superior at effector functions, but at the expense of longevity, hence one of the factors contributing to temporal decay of malaria protective immunity.…”

“…DCs have been isolated in the circulation of Kenyan children afflicted with severe malaria syndromes [445]. Attempts at successful malaria vaccines have so far eluded researchers due to the complexity of acquisition of, and temporal decay of protective memory in humans and experimental animals [95,386,446]. Moreover, recent studies in both murine and humans have elucidated further complexities in Th1 -TFH developmental axis, and with current agreement of the crucial roles of TFH in initiating and sustaining anti-Plasmodium humoral immunity, investigating the involvement of Clec9A + DC in mediating Th1 -TFH responses would be valuable for understanding the roles these cells play in humoral immunity.…”

“…Additionally, in a follow-up study, Opata et al reported all three TEFF subsets were found to have protective capacities as evidenced by rapid proinflammatory cytokine production and protection against PccAS challenge after adoptive transfer of B5 TCR Tg-specific effector cells into RAG KO hosts [386].…”