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CD3+CD5+CD4-CD8-) Alpha/Beta T Cell Receptor-Bearing Cells

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CD3+CD5+CD4-CD8-) Alpha/Beta T Cell Receptor-Bearing Cells Mlsa generated suppressor cells. I. Suppression is mediated by double-negative (CD3+CD5+CD4-CD8-) alpha/beta T cell receptor-bearing cells. This information is current as of October 2, 2021. M Bruley-Rosset, I Miconnet, C Canon and O Halle-Pannenko J Immunol 1990; 145:4046-4052; ; http://www.jimmunol.org/content/145/12/4046 Downloaded from Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription by guest on October 2, 2021 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 © 1990 by American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. 0022-1767/90/14512-4046$02.00/0 THEJOURNAL OF IMMUNOLCGY Vol. 145.4046-4052. No. 12. December 15. 1990 Copyright 0 1990 by The American Association of lmmunologists Printed In U.S.A. Mls" GENERATED SUPPRESSORCELLS I. Suppression is Mediated by Double-Negative (CD3+CDVCD4-CD8-) a/@ T Cell Receptor-Bearing Cells' Grafting of cells from B10.D2 (H-2d)donors into H- The GVHR3 remains a major problem after bone mar- 2 compatible lethally irradiated (DBA/2 x B1O.DZ)Fl row transplantation, even in MHC-compatible donor-re- hostsresults in a severe graft-vs-host reaction cipient combinations. Although elimination of T cells (GVHR), developed against DBA/2 non-H-2 Ag, with from donor marrow inocula reduces incidence of GVHR, Downloaded from only 0 to 10% of animals surviving. This GVHR it also increases the incidence of engraftment failure, mortality rate is dramatically reduced (90 to 100% justifying the search for other treatments thatwill pre- of animals survive) by donor preimmunization vent GVHR development. In our model using adult mice, against Mls" determinants. The protection against grafting of cells from B10.D2 (H-2d)donors intoH-2 com- GVHR correlates with a decreased B10.D2 anti-DBA/ patible lethally irradiated (DBA/2 X BlO.D2)Fl recipients 2 proliferative response in vitro. Bothin vivo and in results in a severe GVHR, with only 0 to 10% of the vitro phenomena are associated with activation of http://www.jimmunol.org/ CD5+suppressor T cells in the spleens of immunized animals surviving (1). Survival is considerably increased mice. The present work was designed to study the by donor immunization, shortlybefore grafting, with par- origin of these suppressor cells and to further char- ent-strain DBA/2 spleen cells (incompatible for numer- acterize their phenotype. Theresults show that sig- ous non-H-2 Ag, including Mls") with a peak of efficiency nificant suppression is not inducible in "B" mice. In seen at 3 to 4 days after immunization (2). Other studies contrast, in mice that were only thymectomizedor showed that abrogation of GVHR mortality is in fact due else pretreated in vivo with anti-CD4 or anti-CD8 to the immunization against Mls" determinants and that mAb, the suppressor cells are activated as effi- it correlates with a decrease of the B10.D2 anti-DBA/2 ciently as in normal mice. Thesuppression of GVHR proliferative response in vitro (3, 4). For protection by guest on October 2, 2021 mortality and proliferative responses in vitro is lost against GVHR to be observed, the expression of Mls" in after depletion from preimmunized splenocytes of grafted recipients is necessary (5)or not (6),depending CD5+ T cells and remains unaltered after depletion upon the genetic combination studied. Therefore, con- of CD4+ or CD8+ T cells or both. Depletion of asialo trasting with the induction phase, the protection is not GM1+ cells removes all NK activity, whereas the specific for Mls" at the effector phase. Both the abroga- suppression is decreased only slightly.FACS analy- tion of GVHR and thedecreased proliferative response in sis showed that double-negative (DN) cells from nor- vitro are associated withthe generation in the spleensof mal and immunized mice contain both CD3+ and immunized donors of noncytotoxic CD5' suppressor T CD3- cells: the vast majority of the CD3+ DN T cells cells (4, 7). These suppressor cells are distinct from veto express the a/@ T cell receptor. Suppression of GVHR T cells effective against thespecific cytotoxic response to and of proliferative responses in vitro are abrogated non-H-2 antigens, and theireffect is detectable in mixing after elimination of CD3' cells. These results sug- experiments (7). The experiments described here were gest that Mls" generated suppressor cells: 1) are designed to characterize better the origin and the phe- derived from post-thymic long-lived T cell precur- notype of the M1s"-generated suppressor cells effective in sors: 2) are low asialo GM-1+ but do not exhibit NK vivo and in vitro. We found that the suppressor cells DN activity: 3) belongto a subset of peripheral CD5+ originate from post-thymic long-lived T cell precursors, T cells bearing a CD3-associated a/&heterodimer. and thatthey areperipheral DN (CD4-CDK)CD5' T cells, bearing a CD3-associated alp-heterodimer of the TcR. Received for publicatton February 26, 1990. Accepted for publication August 24, 1990. The costs of publication of this article were defrayed in part by the MATERIALS AND METHODS payment of page charges. This article must therefore be hereby marked Mice. Female DBA/2 (H-2" Mls'). B10.D2 (H-2" Mlsb),and (DBA/2 advertisement in accordance with 18 U.S.C. Section 1734 solely to indi- x B1O.DS)Fl (H-2"ldMls"@) mice were purchased from Centre Na- cate this fact. tional de la Recherche Scientifique Laboratories. OrliansLa Source. This work was supported by Institut de la Santl et de la Recherche Medicale. Centre National de la Recherche Scientifique, Federation Na- France. tionale des Groupements des Entreprises Francaises dans la Lutte con- Donor immunization and induction of GVHR mortallty. B10.D2 trele Cancer, Fondationpour la Recherche MCdicale, by Grant 6324from donors were immunized by i.v. injection of 2 X lo7 DBA/2 spleen Associatlon pour la Recherche contre le Cancer. and by private funds cells 3 days before grafting (2).(DBA/2 X B1O.DS)Fl adult recipient from Association contre le Cancer en Val de Seine and la Mairie de mice were givena lethal dose (10 Gy) of whole-body irradiation using Vernouillet. a cesium source (RX 30/55 M irradiator; Gravatom Industries Ltd., Address correspondence and reprint requests to Dr. Martine Bruley- Rosset. INSERM U.267 "Immunoglnetique des Allogreffes." Hbpital Paul 3Abbreviations used in this paper: GVHR. graft-vs-host reaction: DN. Brousse. 14 avenuePaul Vaillant Couturier,94800 Villejuif. France. double negative; NS, natural suppressor: PE, phycoerythrin. 4046 Mls“-GENERATED DOUBLE-NEGATIVE SUPPRESSOR CELLS 4047 Gosport, Hampshire, England)at a dose rate of approximately 1 Gy/ were prepared as described in Materials and Methods. min; 24 h after irradiation. they were grafted [i.v.) with lo7 bone Normal and isografted non-“Tx” mice servedas controls. marrow and 8 X 10‘ spleen cells from normal donors. Mortality was recorded five times a wk from day 1 (the day after grafting) to the Two to 3 mo later, the different groups of B10.D2 mice end of the experiment (1 50 days).At that time. surviving mice with were immunized or not by injecting DBA/2 cells. Three strong signsof scleroderma, alopecia, and loss of weight were con- days after immunization, spleencells from these donors sidered to be mice developing GVHR (8).To test the capacity of preimmunized cells to suppress GVHR mortality, different spleen were mixed with normalBlO.D2 bone marrowand spleen cell populations were mixed with normal bone marrow and spleen cells and injected intolethally irradiated (DBA/2 X cells before grafting. Treatment procedures of preimmunized cells B 10.D2)F1 recipients. The spleencells from allgroups of and numbersof cells added are indicated In Results. Preparation of thyrnectomlzed “TX” mice, “B” mfce, and iso- preimmunized mice protect 65 to 95%of recipients (Table grafted mice. Thymectomy of young B10.D2 adult mice was carried I), with one exception: cells from B mice protected only out 2 to 3 mo before grafting. “Bmice were prepared by performing 30% of recipients, but this protectiondoes not differ thymectomy on young B10.D2 adult mice followed by lethal irradia- significantly from that observed with cells from non- tion and reconstitution with T-depleted syngeneic bone marrow cells. Isografted mice consist of lethally irradiated and syngeneic bone preimmunized B mice, and is significantly less efficient marrow reconstituted B10.D2 mice. (p < 0.01) than thatobserved after transferof cells from In vitro depletion.Spleen cells. either unseparatedor nylon wool, preimmunized isografted mice. The generation of sup- nonadherent (T cell-enriched fraction), were incubated for 15 min at 4°C with the appropriatedilution of one of the following antibod- pressor cells is equally efficient in “Tx” and in normal ies: Rat mAb against Thy-1, CD4. CD8 (Biosys), CD5 (Becton Dick- mice. These results indicate that the suppressor cells inson Mountain View, CA), rabbit anti-asialoGM1 antiserum (Wako originate from a long-lived peripheral T cell. Industries) and rat anti-murine CD3 mAb (C363.29B. kindly pro- In vivo administration of either anti-CD4 or anti-CD8 vided by C. A. Janeway). Fresh guineapig complement (diluted 1/8) Downloaded from was added and the mixture was incubated 1 h at 37°C.
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