Mechanisms of maintenance of protection from persistent malaria infection by CD4 effector and effector memory T cells

Abstract

Abstract Generation of CD4 effector memory T cells (Tem) is associated with persistent infections. However, two counterintuitive features we identified obscure any mechanism for the predominance of Tem in chronic infection: that Tem differentiation begins very early in infection, and that Tem do not require persistent infection to survive. Within the first five days of Plasmodium chabaudi infection, the relative proportions of MPEC to SLEC (CD127− CD62Llo) are determined, and predict the ratio of Tcm to Tem. Furthermore, Tem survive as well as Tcm, and better than SLEC, in uninfected recipients. In addition, we determined that Tem are derived from the same memory precursor effector T cells (MPEC, CD127− CD62Lhi) as central memory T cells (Tcm). We have now identified three mechanisms promoting Tem numbers in chronic infection: 1) Tcm can be programmed by chronic infection to produce Tem, even after infection is over low-level, 2) persistent infection promotes turnover of Tem, and 3) some SLEC can also survive to generate Tem. These findings support the feasibility of generating protective Tem by vaccination. Another caveat to generating protection to chronic infection by vaccination, is that protection from disease can be improved by ongoing infection, suggesting a role for SLEC. Therefore, we tested both SLEC and Tmem subsets for contributions to protection, and found that SLEC protect best. Also, decay of SLEC coincides with declining protection as chronic infection is cleared. Nevertheless, one subset of Tem (CD127hiCD62LloCD27−) reduces parasitemia and pathology, and maintains Ifng expression in chronic infection. These findings provide important insight into mechanisms of development and maintenance of immunity to chronic infection.