Human cord blood CD4⁺CD25^hi 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 (Tregs) in utero, cord blood mononuclear cells (CBMC) were obtained from 44 Kenyan newborns of women with and without malaria at delivery. CD4+CD25lo T cells and CD4+CD25hi FOXP3+ cells (T regs) were enriched from CBMC. Treg frequency and HLA-DR expression on Tregs 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-γ, IL-13, IL-10, and/or IL-5 in 50% of samples. Partial depletion of CD25hi cells augmented the Ag-driven IFN-γ production in 69% of subjects with malaria-specific responses and revealed additional Ag-reactive lymphocytes in previously unresponsive individuals (n = 3). Addition of Tregs to CD4+CD25lo cells suppressed spontaneous and malaria Ag-driven production of IFN-γ 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-β did not mediate this suppression. Thus, prenatal exposure to malaria blood-stage Ags induces Tregs that primarily suppress Th1-type recall responses to P. falciparum blood-stage Ags. Persistence of these Tregs postnatally could modify a child's susceptibility to malaria infection and disease. Copyright © 2011 by The American Association of Immunologists, Inc.