ABCB5 Identifies Immunoregulatory Dermal Cells

• Published in: Cell reports (Cambridge) 2015-09, Vol.12 (10), p.1564-1574
• Main Authors: Schatton, Tobias, Yang, Jun, Kleffel, Sonja, Uehara, Mayuko, Barthel, Steven R., Schlapbach, Christoph, Zhan, Qian, Dudeney, Stephen, Mueller, Hansgeorg, Lee, Nayoung, de Vries, Juliane C., Meier, Barbara, Vander Beken, Seppe, Kluth, Mark A., Ganss, Christoph, Sharpe, Arlene H., Waaga-Gasser, Ana Maria, Sayegh, Mohamed H., Abdi, Reza, Scharffetter-Kochanek, Karin, Murphy, George F., Kupper, Thomas S., Frank, Natasha Y., Frank, Markus H.
• Format: Article
• Language: English
• Subjects: Allografts; Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biomarkers - metabolism; Cell Proliferation; Cells, Cultured; Dermis - cytology; Graft Survival; Heart Transplantation; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - metabolism; T-Lymphocytes - immunology; T-Lymphocytes, Regulatory - physiology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.08.010

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. [Display omitted] •Mammalian skin contains dermal immunoregulatory cells (DIRCs)•ABCB5 surface expression constitutes a molecular marker for the isolation of DIRCs•DIRCs suppress alloimmunity and prolong cardiac allograft survival•Efficient DIRC-mediated immunosuppression requires PD-1-mediated Treg induction Schatton et al. identify ABCB5 as a marker of dermal cells in mammalian skin that possess immunoregulatory functions, through engagement of the immune checkpoint molecule PD-1. ABCB5-positive cells, when administered to recipients of heart transplants in preclinical models, prolong graft survival, suggesting promising roles of this cell subset in cellular immunotherapy.