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
    • "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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    ABSTRACT: Regulatory T (Treg ) cells play a crucial role in maintaining peripheral tolerance and preventing autoimmunity. However, they also represent a major barrier to effective anti-tumor immunity and immunotherapy. Consequently, there has been considerable interest in developing approaches that can selectively or preferentially target Treg cells in tumors, while not impacting their capacity to maintain peripheral immune homeostasis. In this review, we describe our current understanding of the mechanisms underlying the recruitment, expansion and suppressive activity of tumor-associated Treg cells, and discuss the approaches used and the challenges encountered in the immunotherapeutic targeting of Treg cells. In addition, we summarize the primary clinical targets and some emerging data on exciting new potential Treg cell-restricted targets. We propose that discovering and understanding mechanisms that are preferentially used by Treg cells within the tumor microenvironment will lead to strategies that selectively target Treg cell-mediated suppression of anti-tumor immunity while maintaining peripheral immune tolerance. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · FEBS Journal
    • "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.
    No preview · Article · Feb 2015 · The EMBO Journal
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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.
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