Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict Journal Article

   

Authors:	Samstein, R. M.; Josefowicz, S. Z.; Arvey, A.; Treuting, P. M.; Rudensky, A. Y.
Article Title:	Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict
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. © 2012 Elsevier Inc.
Keywords:	controlled study; gene sequence; nonhuman; transcription factor foxp3; forkhead transcription factors; animal cell; mouse; mammalia; animals; mice; animal tissue; radiation; embryo; animal experiment; inflammation; histology; animalia; immunological tolerance; regulatory t lymphocyte; immune tolerance; molecular evolution; t-lymphocytes, regulatory; pregnancy; cell count; fetus; lymphocytic infiltration; mammals; alloantigen; model; placenta; mother fetus relationship; enhancer region; enhancer elements, genetic; eutheria; mating; conserved noncoding sequence 1; interspersed repeat; placental mammals; opossums
Journal Title:	Cell
Volume:	150
Issue:	1
ISSN:	0092-8674
Publisher:	Cell Press
Date Published:	2012-07-06
Start Page:	29
End Page:	38
Language:	English
DOI:	10.1016/j.cell.2012.05.031
PROVIDER:	scopus
PUBMED:	22770213
PMCID:	PMC3422629
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84863619688&partnerID=40&md5=131891783a19765b2d469930975b9292
Notes:	--- - "Cited By (since 1996): 1" - "Export Date: 1 August 2012" - "CODEN: CELLB" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/31987