title: Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17beta-estradiol.
abstract: CD4(+)CD25(high) regulatory T cells (Tregs) are implicated in the maintenance of murine pregnancy. However, reports regarding circulating Treg frequencies in human pregnancy are inconsistent, and the functionality and phenotype of these cells in pregnancy have not been clarified. The aim of this study was to determine the frequency, phenotype, and function of circulating Tregs in the second trimester of human pregnancy and the influence of progesterone and 17beta-estradiol on Treg phenotype and frequency. Based on expressions of Foxp3, CD127, and HLA-DR as determined by multicolor flow cytometry, we defined a proper CD4(dim)CD25(high) Treg population and showed, in contrast to most previous reports, that this population was reduced in second trimester of pregnancy. Unexpectedly, Foxp3 expression was decreased in the Treg, as well as in the CD4(+) population. These changes could be replicated in an in vitro system resembling the pregnancy hormonal milieu, where 17beta-estradiol, and in particular progesterone, induced, in line with the pregnancy situation, a reduction of CD4(dim)CD25(high)Foxp3(+) cells in PBMC from nonpregnant women. By coculturing FACS-sorted Tregs and autologous CD4(+)CD25(-) responder cells, we showed that Tregs from pregnant women still displayed the same suppressive capacity as nonpregnant women in terms of suppressing IL-2, TNF-alpha, and IFN-gamma secretion from responder cells while efficiently producing IL-4 and IL-10. Our findings support the view of hormones, particularly progesterone, as critical regulators of Tregs in pregnancy. Furthermore, we suggest that in the light of the results of this study, early data on circulating Treg frequencies in pregnancy need reevaluation.
authors.affiliation: Department of Clinical and Experimental Medicine, Linkööping University, Sweden. jenny.mjosberg@liu.se
authors.forename: Jenny
authors.initials: J
authors.lastname: Mjösberg
authors.forename: Judit
authors.initials: J
authors.lastname: Svensson
authors.forename: Emma
authors.initials: E
authors.lastname: Johansson
authors.forename: Lotta
authors.initials: L
authors.lastname: Hellström
authors.forename: Rosaura
authors.initials: R
authors.lastname: Casas
authors.forename: Maria C
authors.initials: MC
authors.lastname: Jenmalm
authors.forename: Roland
authors.initials: R
authors.lastname: Boij
authors.forename: Leif
authors.initials: L
authors.lastname: Matthiesen
authors.forename: Jan-Ingvar
authors.initials: JI
authors.lastname: Jönsson
authors.forename: Göran
authors.initials: G
authors.lastname: Berg
authors.forename: Jan
authors.initials: J
authors.lastname: Ernerudh
mesh_terms: D000328:Adult; D015704:CD4 Antigens / Q000096:biosynthesis / Q000097:blood; D016516:CD4-CD8 Ratio; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000097:blood; D006801:Humans; D016130:Immunophenotyping / Q000379:methods; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000097:blood; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000096:biosynthesis / Q000097:blood; D011262:Pregnancy Trimester, Second / Q000276:immunology*; D011374:Progesterone / Q000494:pharmacology / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D011257:Pregnancy Proteins; D011374:Progesterone; D004958:Estradiol