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


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,
    • "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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    ABSTRACT: Peripheral induction of regulatory T (Treg) cells provides essential protection from inappropriate immune responses. CD4(+) T cells that lack endogenous miRNAs are impaired to differentiate into Treg cells, but the relevant miRNAs are unknown. We performed an overexpression screen with T-cell-expressed miRNAs in naive mouse CD4(+) T cells undergoing Treg differentiation. Among 130 candidates, the screen identified 29 miRNAs with a negative and 10 miRNAs with a positive effect. Testing reciprocal Th17 differentiation revealed specific functions for miR-100, miR-99a and miR-10b, since all of these promoted the Treg and inhibited the Th17 program without impacting on viability, proliferation and activation. miR-99a cooperated with miR-150 to repress the expression of the Th17-promoting factor mTOR. The comparably low expression of miR-99a was strongly increased by the Treg cell inducer "retinoic acid", and the abundantly expressed miR-150 could only repress Mtor in the presence of miR-99a. Our data suggest that induction of Treg cell differentiation is regulated by a miRNA network, which involves cooperation of constitutively expressed as well as inducible miRNAs. © 2015 The Authors.
    The EMBO Journal 02/2015; 34(9). DOI:10.15252/embj.201489589 · 10.43 Impact Factor
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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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    ABSTRACT: In this review, we first revisit the original concept of "suppressor T-cells" in pregnancy, put it in a historical perspective, and then highlight the main data that licensed its resurrection and revision into the concept of "regulatory T-cells" (Tregs) in pregnancy. We review the evidence for a major role of Tregs in murine and human pregnancy and discuss Treg interactions with dendritic and uterine natural killer cells, other players of maternal-fetal tolerance. Finally, we highlight what we consider as the most important questions in the field.
    Frontiers in Immunology 08/2014; 5:389. DOI:10.3389/fimmu.2014.00389
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    • "Thus, one could speculate that mTreg-specific for intermittently expressed antigens are a mechanism devised to face the challenges and changes that accompany sexual reproduction in mammals. In this way, mTreg are similar to pTreg, which seem to have evolved to mitigate the maternal–fetal conflict (152). Subsequently, both regulatory cell types may evolutionarily have been adapted to mediate microbiota-specific tolerance (33). "
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    ABSTRACT: Foxp3(+) regulatory T cells (Treg cells) are essential for establishing and maintaining self-tolerance, and also inhibit immune responses to innocuous environmental antigens. Imbalances and dysfunction in Treg cells lead to a variety of immune-mediated diseases, as deficits in Treg cell function contribute to the development autoimmune disease and pathological tissue damage, whereas overabundance of Treg cells can promote chronic infection and tumorigenesis. Recent studies have highlighted the fact that Treg cells themselves are a diverse collection of phenotypically and functionally specialized populations, with distinct developmental origins, antigen-specificities, tissue-tropisms, and homeostatic requirements. The signals directing the differentiation of these populations, their specificities and the mechanisms by which they combine to promote organ-specific and systemic tolerance, and how they embody the emerging property of regulatory memory are the focus of this review.
    Frontiers in Immunology 07/2014; 5:333. DOI:10.3389/fimmu.2014.00333
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