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

TitleExtrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict.
Publication TypeJournal Article
Year of Publication2012
AuthorsSamstein RM, Josefowicz SZ, Arvey A, Treuting PM, Rudensky AY
Date Published2012 Jul 06
KeywordsAnimals, Enhancer Elements, Genetic, Female, Fetus, Forkhead Transcription Factors, Humans, Immune Tolerance, Male, Mammals, Mice, Opossums, Placenta, Pregnancy, T-Lymphocytes, Regulatory

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.

Alternate JournalCell
PubMed ID22770213
PubMed Central IDPMC3422629
Grant ListGM07739 / GM / NIGMS NIH HHS / United States
R37 AI21609 / AI / NIAID NIH HHS / United States
DK091968 / DK / NIDDK NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
Related Faculty: 
Steven Josefowicz, Ph.D.

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