Human Cord Blood CD4+CD25hi Regulatory T Cells Suppress Prenatally Acquired T Cell Responses to Plasmodium falciparum Antigens

In malaria endemic regions, a fetus is often exposed in utero to Plasmodium falciparum blood-stage Ags. In some newborns, this can result in the induction of immune suppression. We have previously shown these modulated immune responses to persist postnatally, with a subsequent increase in a child's susceptibility to infection. To test the hypothesis that this immune suppression is partially mediated by malaria-specific regulatory T cells (T-regs) in utero, cord blood mononuclear cells (CBMC) were obtained from 44 Kenyan newborns of women with and without malaria at delivery. CD4(+)CD25(lo) T cells and CD4(+)CD25(hi) FOXP3(+) cells (T-regs) were enriched from CBMC. T-reg frequency and HLA-DR expression on T-regs were significantly greater for Kenyan as compared with North American CBMC (p < 0.01). CBMC/CD4(+) T cells cultured with P. falciparum blood-stage Ags induced production of IFN-gamma, IL-13, IL-10, and/or IL-5 in 50% of samples. Partial depletion of CD25(hi) cells augmented the Ag-driven IFN-gamma production in 69% of subjects with malaria-specific responses and revealed additional Ag-reactive lymphocytes in previously unresponsive individuals (n = 3). Addition of T-regs to CD4(+)CD25(lo) cells suppressed spontaneous and malaria Ag-driven production of IFN-gamma in a dose-dependent fashion, until production was completely inhibited in most subjects. In contrast, T-regs only partially suppressed malaria-induced Th2 cytokines. IL-10 or TGF-beta did not mediate this suppression. Thus, prenatal exposure to malaria blood-stage Ags induces T-regs that primarily suppress Th1-type recall responses to P. falciparum blood-stage Ags. Persistence of these T-regs post-natally could modify a child's susceptibility to malaria infection and disease. The Journal of Immunology, 2011, 186: 2780-2791.