title: Human cord blood CD4+CD25hi regulatory T cells suppress prenatally acquired T cell responses to Plasmodium falciparum antigens.
abstract: 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-γ, IL-13, IL-10, and/or IL-5 in 50% of samples. Partial depletion of CD25(hi) 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 T(regs) to CD4(+)CD25(lo) 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 T(regs) that primarily suppress Th1-type recall responses to P. falciparum blood-stage Ags. Persistence of these T(regs) postnatally could modify a child's susceptibility to malaria infection and disease.
authors.affiliation: Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH 44106, USA. mariamackroth@gmx.de
authors.forename: Maria S
authors.initials: MS
authors.lastname: Mackroth
authors.forename: Indu
authors.initials: I
authors.lastname: Malhotra
authors.forename: Peter
authors.initials: P
authors.lastname: Mungai
authors.forename: Davy
authors.initials: D
authors.lastname: Koech
authors.forename: Eric
authors.initials: E
authors.lastname: Muchiri
authors.forename: Christopher L
authors.initials: CL
authors.lastname: King
mesh_terms: D000595:Amino Acid Sequence; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology* / Q000469:parasitology; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory; D007231:Infant, Newborn; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis* / Q000097:blood; D008288:Malaria / Q000097:blood / Q000276:immunology / Q000473:pathology; D020066:Merozoite Surface Protein 1 / Q000097:blood*; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000276:immunology*; D012269:Ribosomal Proteins / Q000097:blood*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*
chemical_list: C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D020066:Merozoite Surface Protein 1; D012269:Ribosomal Proteins; C054675:ribosomal protein P0