Evidence for limited activation of distinct CD4+T cell subsets in response to the Plasmodium falciparum circumsporozoite protein in Papua New Guinea

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Abstract
Both CD4⁺ and CD8⁺ T cells, as well as antibody, are known to be important in sporozoite immunity. Data from animal studies suggest that cytokines, in particular γ-interferon and interleukin-6, are involved. The interplay of these various factors and their importance in vaccine development has, however, not yet been elucidated. In this study, we have studied cellular and humoral responses of individuals naturally exposed to malaria in a highly endemic region of Papua New Guinea to the circumsporozoite protein of Plasmodium falciparum, a prime vaccine candidate antigen. A paucity of any CD4⁺ lymphoproliferative response to this protein by Papua New Guineans was notable which parallels our recent observation of a paucity of CD8⁺ T cell response and contrasts markedly with the responses of other endemic populations. There was nevertheless a significant antibody response to the central conserved B cell epitope, (NANP)ₙ, as well as to other critical epitopes. An inverse relationship between γ-interferon production and interleukin-6 production and a positive correlation between γ-interferon production and CS peptide-specific lymphoproliferation was observed. High levels of peptide-specific IL-6 production were associated with high levels of peptide-specific serum antibodies. Our data provide evidence for the limited activation of distinct CD4⁺ T cell subsets and for the existence of functionally distinct subpopulations of human CD4⁺ T cells with respect to cytokines known to be important in sporozoite immunity