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Human Placental Trophoblasts Regulatory T Cells by + Activation Activation of CD8+ Regulatory T Cells by Human Placental Trophoblasts Ling Shao, Adam R. Jacobs, Valrie V. Johnson and Lloyd Mayer This information is current as of September 23, 2021. J Immunol 2005; 174:7539-7547; ; doi: 10.4049/jimmunol.174.12.7539 http://www.jimmunol.org/content/174/12/7539 Downloaded from References This article cites 50 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/174/12/7539.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 23, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Activation of CD8؉ Regulatory T Cells by Human Placental Trophoblasts1 Ling Shao,2* Adam R. Jacobs,† Valrie V. Johnson,† and Lloyd Mayer* The immunological basis by which a mother tolerates her semi-allogeneic fetus remains poorly understood. Several mechanisms are likely to contribute to this phenomenon including active immune regulation by regulatory T cells. In this article, we report that human placental trophoblasts activate a clonal population of CD8؉ T cells with regulatory function. These cells are not MHC class I restricted, but require costimulation through a member of the carcinoembryonic Ag family present on early gestation tropho- blasts. These regulatory T cells express the mucosal markers CD101 and CD103 and display selective usage of the TCR gene V␤9. ␤CD8؉ T cells isolated from the peripheral blood of pregnant mothers (16–28 wk) also demonstrate expansions in the same V family (V␤9), signaling a possible role for these cells in preventing fetal rejection in vivo. We have previously characterized a ؉ subset of CD8 regulatory T cells activated by the combination of the nonclassical class I molecule CD1d and a costimulatory Downloaded from molecule of the carcinoembryonic Ag family present on the intestinal epithelium. These data support the concept that distinct regulatory T cell populations exist at different sites and may be regulated locally by unique restriction elements, costimulatory signals, and Ags. The Journal of Immunology, 2005, 174: 7539–7547. llogeneic tissue grafts are typically rejected rapidly and commensal flora at the interface between the external environment require exogenous immunosuppressive medications to and the mucosal immune system. Interestingly, patients with in- http://www.jimmunol.org/ A be tolerated. In contrast, the human fetus, which resem- flammatory bowel disease are deficient in the expression of the bles a semi-allogeneic graft, is accepted by the maternal immune CEA subfamily costimulatory molecule, which correlates with an system in the majority of cases without intervention. Potential inability of these patients to be tolerized to orally administered mechanisms underlying this phenomena are likely to be Ags (12). complex (1). Regulatory T cells (reviewed in Ref. 13) comprise a heteroge- Anatomically, placental trophoblasts occupy a unique position neous class of cells that suppress immune responses via cognate at the interface between mother and child. These epithelial cells interactions (CD4ϩCD25ϩ), soluble factors such as TGF-␤ or possess several intriguing features that suggest a role for these IL-10 (Th3 and Tr1 cells, respectively), or some combination of cells in preventing fetal rejection. Trophoblasts express little or no the two. These cells appear to play a role in controlling inflam- by guest on September 23, 2021 classical MHC class I (HLA-A, -B, and -C) (2–5), but do express matory immune responses in a number of settings including auto- a number of nonclassical MHC class I molecules. Examples in- immune and chronic inflammatory diseases. Recently, a role for clude HLA-E (6) and HLA-G (7, 8), which can modulate the in- regulatory T cells has been demonstrated in maintaining fetal tol- nate immune response and prevent NK (6) and NK T cell (9)- erance as well. CD4ϩCD25ϩ regulatory T cells play a critical role mediated cytotoxicity. Additionally, trophoblasts have been in mice during pregnancy after allogeneic matings (14). In hu- recently shown to express the nonclassical MHC class I molecule, mans, CD4ϩCD25ϩ cells expressing the regulatory transcription CD1d, on the surface of first-trimester human trophoblasts (10). factor FoxP3 (15), OX-40, and glucocorticoid-induced TNFR fam- We have previously described a subset of CD8ϩ regulatory T ily-related gene are expanded in the peripheral blood as well as at cells in humans that is restricted by CD1d and a costimulatory the maternal-fetal interface (16), implying an important role for molecule of the carcinoembryonic Ag (CEA)3 family expressed on these cells in fetal tolerance. intestinal epithelial cells (IEC). These cells use a restricted TCR In this report, we show that trophoblasts can activate a subset of repertoire (V␤5.1/V␣18), are CD28Ϫ, and can suppress immune CD8ϩ T cells that are independent of classical MHC class I but are responses in vitro (11). In the intestine, these cells may play an dependent upon a CEA subfamily member. These T cells have a important role in controlling inflammatory responses to normal restricted TCR repertoire, coexpress the mucosal markers CD101 and CD103, and demonstrate in vitro regulatory properties. Fi- nally, we provide evidence that these CD8ϩ T cell subsets are *Immunobiology Center and †Department of Obstetrics and Gynecology, Mount Si- expanded in the peripheral blood of pregnant mothers, suggesting nai School of Medicine, New York, NY 10029 a potential role for these cells in vivo. Received for publication October 18, 2004. Accepted for publication April 8, 2005. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Materials and Methods Trophoblast isolation 1 This work was supported by Public Health Service Grants AI23504, AI24671, AI44236, and AI07605 (to L.M.). Placentae from 7- to 18-wk elective abortions performed at the Mount 2 Address correspondence and reprint requests to Dr. Ling Shao, Mount Sinai School Sinai Medical Center or full-term (38–40 wk) pregnancies were collected of Medicine, 1 Gustave L. Levy Place, Department of Immunobiology, Box 1089, in accordance with the Mount Sinai Institutional Review Board guidelines. New York, NY 10029. E-mail address: [email protected] Trophoblasts were isolated as described previously (17, 18), with modifi- 3 Abbreviations used in this paper: CEA, carcinoembryonic Ag; IEC, intestinal epi- cations. Briefly, placental specimens were washed twice in PBS, and mem- thelial cell; FasL, Fas ligand; BGP, biliary glycoprotein; NCA, nonspecific cross- branes were manually removed. The placenta was then digested in PBS reacting Ag. containing 1.5 mg/ml Dispase (Roche Applied Science) and 300 ␮g/ml Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 7540 TROPHOBLASTS ACTIVATE CD8ϩ REGULATORY T CELLS DNase I (Calbiochem) for 15 min at 37°C with gentle agitation. Superna- perature. After extensive washing, blots were developed with SuperSignal tants were harvested and layered on FCS (Omega Scientific) and centri- (Pierce). fuged for 15 min at 1200 ϫ g. Pellets were resuspended in PBS and layered on a discontinuous Percoll density gradient (25/45/60%) and centrifuged Immunohistochemistry for 20 min at 1200 ϫ g. Trophoblasts were isolated from the 25/45% Percoll interface and washed twice in AIM-V serum-free medium (Invitro- Placentae were washed twice in sterile PBS. Specimens were then snap gen Life Technologies). In some cases, cells were preincubated with Abs frozen in OCT compound (Miles) in liquid nitrogen. Eight-micrometer against CD1d (mAb D5, MsIgG2b; a kind gift from Drs. R. Blumberg frozen sections were cut and immediately fixed in 4% PBS-buffered for- (Brigham and Women’s Hospital, Boston, MA) and S. Balk (Beth Israel malin overnight. Sections were rinsed briefly in PBS, and the tissue was Deaconess Medical Center, Boston, MA)), gp180 (mAb B9, MsIgG1; see outlined by an ImmEdge hydrophobic pen (Vector Laboratories). Nonspe- Ref. 19), pan-MHC-I (W6/32, MsIgG2a), or isotype controls (BD Pharm- cific-Ab activity was blocked with normal horse serum for 30 min at room ingen) for 60 min at 4°C. Excess Ab was removed by extensive washing in temperature. Slides were incubated with 10 ␮g of either the B9 mAb or PBS before coculture. isotype control (IgG1; BD Pharmingen) for2hatroom temperature. Bi- otinylated secondary Abs and streptavidin-HRP from the Vectastain ABC T cell isolation and T trophoblast coculture (avidin-biotin complex) kit was added (Vector Laboratories) for 45 min at Blood from pregnant and nonpregnant donors was obtained with informed room temperature.
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