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

Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH 44106, USA.
The Journal of Immunology (Impact Factor: 4.92). 03/2011; 186(5):2780-91. DOI: 10.4049/jimmunol.1001188
Source: PubMed


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.

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    • "Finally, such small parasite components may be able to cross the placental barrier and thus explain and contribute to the induction of Tregs in cord blood even in the absence of direct cord blood parasitemia. Indeed, in some studies levels of Tregs have been found to be elevated in neonates born to mothers who had experienced malaria episodes during pregnancy (Brustoski et al., 2006; Mackroth et al., 2011), while in other studies, ex vivo cord blood Treg frequencies were unaffected by placental malaria and only increased only upon in vitro stimulation with iRBC extract (Flanagan et al., 2010; Soulard et al., 2011). It is yet unclear whether Treg induction during a single Plasmodium infection predisposes the immune system to heightened regulatory responses at the next encounter with the parasite, but in utero exposure to Treg-inducing parasite components may prime the fetus's immune system to respond with a less inflammatory response upon re-exposure to malaria-antigens (Malhotra et al., 2009; Flanagan et al., 2010). "
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    • "Other immunoregulatory networks likely exist with heavy infections such as development of atypical and potentially suppressive B cells (Pierce, 2009; Weiss et al., 2009) and suppression of antigen-presenting cell functions akin to endotoxin tolerance (Boutlis et al., 2006). Immune tolerance can also result from in utero exposure to malaria or their soluble products (King et al., 2002; Mackroth et al., 2011; Malhotra et al., 2008, 2009; Metenou et al., 2007) that can persist into early childhood (Malhotra et al., 2009). Malaria in pregnancy is much less common and if present, is less likely to cause altered placental dysfunction for Pv compared to Pf (Rogerson et al., 2007; ter Kuile and Rogerson, 2008). "
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    • "The abnormal production of Tregs could also represent an immunosuppressing factor in itself. Indeed, several studies now indicate that an excessive Treg presence may impede immuno-surveillance against tumor cells and may suppress the ability of CD4 + effector T cells to, for example, eliminate parasites (Belkaid et al., 2002; Mackroth et al., 2011). More recently, the contribution of regulatory B cells in experimental stroke has been uncovered (Ren et al., 2011). "
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