title: ABCB5 Identifies Immunoregulatory Dermal Cells.
abstract: Cell-based strategies represent a new frontier in the treatment of immune-mediated disorders. However, the paucity of markers for isolation of molecularly defined immunomodulatory cell populations poses a barrier to this field. Here, we show that ATP-binding cassette member B5 (ABCB5) identifies dermal immunoregulatory cells (DIRCs) capable of exerting therapeutic immunoregulatory functions through engagement of programmed cell death 1 (PD-1). Purified Abcb5(+) DIRCs suppressed T cell proliferation, evaded immune rejection, homed to recipient immune tissues, and induced Tregs in vivo. In fully major-histocompatibility-complex-mismatched cardiac allotransplantation models, allogeneic DIRCs significantly prolonged allograft survival. Blockade of DIRC-expressed PD-1 reversed the inhibitory effects of DIRCs on T cell activation, inhibited DIRC-dependent Treg induction, and attenuated DIRC-induced prolongation of cardiac allograft survival, indicating that DIRC immunoregulatory function is mediated, at least in part, through PD-1. Our results identify ABCB5(+) DIRCs as a distinct immunoregulatory cell population and suggest promising roles of this expandable cell subset in cellular immunotherapy.
authors: Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA; Transplantation Research Center, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Tobias
authors: T
authors: Schatton
authors: Transplantation Research Center, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA 02115, USA; Institute of Organ Transplantation, Huazhong University of Science and Technology, Wuhan 430074, China.
authors: Jun
authors: J
authors: Yang
authors: Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Sonja
authors: S
authors: Kleffel
authors: Transplantation Research Center, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Mayuko
authors: M
authors: Uehara
authors: Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Steven R
authors: SR
authors: Barthel
authors: Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Dermatology, University of Bern, Bern 3012, Switzerland.
authors: Christoph
authors: C
authors: Schlapbach
authors: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Qian
authors: Q
authors: Zhan
authors: Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Stephen
authors: S
authors: Dudeney
authors: Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Hansgeorg
authors: H
authors: Mueller
authors: Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Nayoung
authors: N
authors: Lee
authors: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm 89077, Germany.
authors: Juliane C
authors: JC
authors: de Vries
authors: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm 89077, Germany.
authors: Barbara
authors: B
authors: Meier
authors: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm 89077, Germany.
authors: Seppe
authors: S
authors: Vander Beken
authors: Rheacell GmbH & Co. KG, Heidelberg 69120, Germany.
authors: Mark A
authors: MA
authors: Kluth
authors: Rheacell GmbH & Co. KG, Heidelberg 69120, Germany.
authors: Christoph
authors: C
authors: Ganss
authors: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Arlene H
authors: AH
authors: Sharpe
authors: Department of Surgery, University of Würzburg Medical School, Würzburg 97080, Germany.
authors: Ana Maria
authors: AM
authors: Waaga-Gasser
authors: Transplantation Research Center, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Mohamed H
authors: MH
authors: Sayegh
authors: Transplantation Research Center, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Reza
authors: R
authors: Abdi
authors: Department of Dermatology and Allergic Diseases, University of Ulm, Ulm 89077, Germany.
authors: Karin
authors: K
authors: Scharffetter-Kochanek
authors: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: George F
authors: GF
authors: Murphy
authors: Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Thomas S
authors: TS
authors: Kupper
authors: Transplantation Research Center, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Boston VA Healthcare System, West Roxbury, MA 02132, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors: Natasha Y
authors: NY
authors: Frank
authors: Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA; Transplantation Research Center, Boston Children's Hospital and Brigham and Women's Hospital, Boston, MA 02115, USA; School of Medical Sciences, Edith Cowan University, Joondalup, WA 6027, Australia. Electronic address: markus.frank@childrens.harvard.edu.
authors: Markus H
authors: MH
authors: Frank
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D064591:Allografts; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology; D006085:Graft Survival; D016027:Heart Transplantation; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
chemical_list: C480744:ABCB5 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015415:Biomarkers; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor