Article

Extrathymic Generation of Regulatory T Cells in Placental Mammals Mitigates Maternal-Fetal Conflict

Howard Hughes Medical Institute and Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Cell (Impact Factor: 32.24). 07/2012; 150(1):29-38. DOI: 10.1016/j.cell.2012.05.031
Source: PubMed

ABSTRACT

Regulatory T (Treg) cells, whose differentiation and function are controlled by X chromosome-encoded transcription factor Foxp3, are generated in the thymus (tTreg) and extrathymically (peripheral, pTreg), and their deficiency results in fatal autoimmunity. Here, we demonstrate that a Foxp3 enhancer, conserved noncoding sequence 1 (CNS1), essential for pTreg but dispensable for tTreg cell generation, is present only in placental mammals. CNS1 is largely composed of mammalian-wide interspersed repeats (MIR) that have undergone retrotransposition during early mammalian radiation. During pregnancy, pTreg cells specific to a model paternal alloantigen were generated in a CNS1-dependent manner and accumulated in the placenta. Furthermore, when mated with allogeneic, but not syngeneic, males, CNS1-deficient females showed increased fetal resorption accompanied by increased immune cell infiltration and defective remodeling of spiral arteries. Our results suggest that, during evolution, a CNS1-dependent mechanism of extrathymic differentiation of Treg cells emerged in placental animals to enforce maternal-fetal tolerance.

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Available from: Steven Zvi Josefowicz
    • "and tissue pathology[6,10], whereas pT reg cells are thought to limit local immune pathologies at environmental boundaries (e.g. mucosal or fetus-maternal interfaces[11,12]). While the presence of pT reg cells in the tumor microenvironment and their functional impact is an important topic (as reviewed in[13,14]), for the purpose of this review we will not distinguish between pT reg and tT reg cells and instead will discuss the impact of T reg cells on tumors in general. "
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    • "They also differentiate in the periphery from naive T cells to generate tolerance to foreign antigens present in the food or in the air (Zhang et al, 2001; Chen et al, 2003; Kretschmer et al, 2005). Consequently, these peripheral regulatory T cells are of critical importance at mucosal surfaces but also contribute to feto-maternal tolerance (Josefowicz et al, 2012; Samstein et al, 2012). The differentiation of peripheral regulatory T cells can be recapitulated partially in vitro by stimulation of naive CD4 + T cells via the T-cell receptor and the co-stimulatory receptor CD28 in the presence of TGFb and IL-2 (Chen et al, 2003; Zheng et al, 2004). "
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    • "Similar to Tregs, uNK cell numbers vary during the estrus cycle. Recent results from Rudensky’s group have highlighted a defect in spiral artery formation in mice lacking pTregs (85). Absence of pTregs determines fetal demise in their model. "
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