TY - JOUR
T1 - Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict
AU - Samstein, Robert M.
AU - Josefowicz, Steven Z.
AU - Arvey, Aaron
AU - Treuting, Piper M.
AU - Rudensky, Alexander Y.
N1 - Funding Information:
We would like to thank J. Gerard, Y. Liang, D. Canner, and M. Samstein; Z. Williams for helpful discussion; S. Gelber for review of histology; and P. Samollow and J. Vandeberg for providing opossum genomic DNA. R.M.S. was supported by NIH DK091968 and MSTP grant GM07739. A.Y.R. was supported by NIH grant R37 AI21609. A.Y.R. is an investigator with the Howard Hughes Medical Institute.
PY - 2012/7/6
Y1 - 2012/7/6
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84863619688
U2 - 10.1016/j.cell.2012.05.031
DO - 10.1016/j.cell.2012.05.031
M3 - Article
C2 - 22770213
AN - SCOPUS:84863619688
SN - 0092-8674
VL - 150
SP - 29
EP - 38
JO - Cell
JF - Cell
IS - 1
ER -