Tobias Schatton, Jun Yang, Sonja Kleffel, Mayuko Uehara, Steven R. Barthel, Christoph Schlapbach, Qian Zhan, Stephen Dudeney, Hansgeorg Mueller, Nayoung Lee, Juliane C. de Vries, Barbara Meier, Seppe Vander Beken, Mark A. Kluth, Christoph Ganss, Arlene H. Sharpe, Ana Maria Waaga-Gasser, Mohamed H. Sayegh, Reza Abdi, Karin Scharffetter-Kochanek, George F. Murphy, Thomas S. Kupper, Natasha Y. Frank, Markus H. Frank

• 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 toCell-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.…