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https://hdl.handle.net/2440/121178
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Type: | Journal article |
Title: | Thymus-derived regulatory T cells exhibit Foxp3 epigenetic modification and phenotype attenuation after mating in mice |
Author: | Moldenhauer, L.M. Schjenken, J.E. Hope, C.M. Green, E.S. Zhang, B. Eldi, P. Hayball, J.D. Barry, S.C. Robertson, S.A. |
Citation: | Journal of Immunology, 2019; 203(3):647-657 |
Publisher: | American Association of Immunologists |
Issue Date: | 2019 |
ISSN: | 0022-1767 1550-6606 |
Statement of Responsibility: | Lachlan M. Moldenhauer, John E. Schjenken, Christopher M. Hope, Ella S. Green, Bihong Zhang, Preethi Eldi, John D. Hayball, Simon C. Barry and Sarah A. Robertson |
Abstract: | Regulatory T cells (Tregs) are essential for maternal tolerance in allogeneic pregnancy. In preeclampsia, Tregs are fewer and display aberrant phenotypes, particularly in the thymic Treg (tTreg) compartment, potentially because of insufficient priming to male partner alloantigens before conception. To investigate how tTregs as well as peripheral Tregs (pTregs) respond to male partner seminal fluid, Foxp3⁺CD4⁺ Tregs were examined in the uterus and uterus-draining lymph nodes in virgin estrus mice and 3.5 d postcoitum. Mating elicited 5-fold increases in uterine Tregs accompanied by extensive Treg proliferation in the uterus-draining lymph nodes, comprising 70% neuropilin 1⁺ tTregs and 30% neuropilin 1⁻ pTregs. Proliferation marker Ki67 and suppressive competence markers Foxp3 and CTLA4 were induced after mating in both subsets, and Ki67, CTLA4, CD25, and GITR were higher in tTregs than in pTregs. Analysis by t-stochastic neighbor embedding confirmed phenotypically distinct tTreg and pTreg clusters, with the proportion of tTregs but not pTregs among CD4⁺ T cells expanding in response to seminal fluid. Bisulphite sequencing revealed increased demethylation of the Treg-specific demethylation region in the Foxp3 locus in tTregs but not pTregs after mating. These data show that tTregs and pTregs with distinct phenotypes both respond to seminal fluid priming, but the Foxp3 epigenetic signature is uniquely increased in tTregs. We conclude that reproductive tract tTregs as well as pTregs are sensitive to local regulation by seminal fluid, providing a candidate mechanism warranting evaluation for the potential to influence preeclampsia susceptibility in women. |
Keywords: | Uterus Lymph Nodes Thymus Gland Semen Animals Mice, Inbred BALB C Mice, Inbred C57BL Mice Pre-Eclampsia Neuropilin-1 Cell Proliferation Epigenesis, Genetic Pregnancy Female Male T-Lymphocytes, Regulatory Forkhead Transcription Factors Sexual Behavior, Animal Interleukin-2 Receptor alpha Subunit Glucocorticoid-Induced TNFR-Related Protein CTLA-4 Antigen |
Rights: | Copyright © 2019 by The American Association of Immunologists, Inc. |
DOI: | 10.4049/jimmunol.1900084 |
Grant ID: | NHMRC |
Published version: | http://dx.doi.org/10.4049/jimmunol.1900084 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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