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.
authors: Howard Hughes Medical Institute and Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Robert M
authors: RM
authors: Samstein
authors: Steven Z
authors: SZ
authors: Josefowicz
authors: Aaron
authors: A
authors: Arvey
authors: Piper M
authors: PM
authors: Treuting
authors: Alexander Y
authors: AY
authors: Rudensky
mesh_terms: D000818:Animals; D004742:Enhancer Elements, Genetic; D005260:Female; D005333:Fetus / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance; D008297:Male; D008322:Mammals / Q000235:genetics / Q000276:immunology*; D051379:Mice; D009893:Opossums; D010920:Placenta / Q000166:cytology* / Q000276:immunology*; D011247:Pregnancy / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse