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조회929

University of Michigan

J. Clin. Invest., Published March 20, 2017 | doi:10.1172/JCI89535 Fibroblastic niches prime T cell alloimmunity through Delta-like Notch ligands

Abstract

Jooho Chung,^1,2 Christen L. Ebens,^2,3,4 Eric Perkey,^1,2 Vedran Radojcic,^2,5 Ute Koch,⁶ Leonardo Scarpellino,⁷ Alexander Tong,⁸ Frederick Allen,⁸ Sherri Wood,⁹ Jiane Feng,⁹ Ann Friedman,² David Granadier,² Ivy T. Tran,² Qian Chai,¹⁰ Lucas Onder,¹⁰ Minhong Yan,¹¹ Pavan Reddy,⁵ Bruce R. Blazar,⁴ Alex Y. Huang,⁸ Todd V. Brennan,¹² D. Keith Bishop,⁹ Burkhard Ludewig,¹⁰ Christian W. Siebel,¹¹ Freddy Radtke,⁶ Sanjiv A. Luther,⁷ and Ivan Maillard^2,5
¹Graduate Program in Cellular and Molecular Biology, ²Life Sciences Institute, and ³Division of Hematology-Oncology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA. ⁴ Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA. ⁵Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. ⁶Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland. ⁷Department of Biochemistry, University of Lausanne, Epalinges, Switzerland. ⁸Medical Scientist Training Program and Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio, USA. ⁹Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA. ¹⁰Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland. ¹¹Genentech, South San Francisco, California, USA. ¹²Department of Surgery, Duke University, Durham, North Carolina, USA.

Authorship note: J. Chung and C.L. Ebens contributed equally to this work.

Address correspondence to: Ivan Maillard, 6382A Life Sciences Institute, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109-2216, USA.

Abstract
Alloimmune T cell responses induce graft-versus-host disease (GVHD), a serious complication of allogeneic bone marrow transplantation (allo-BMT). Although Notch signaling mediated by Delta-like 1/4 (DLL1/4) Notch ligands has emerged as a major regulator of GVHD pathogenesis, little is known about the timing of essential Notch signals and the cellular source of Notch ligands after allo-BMT. Here, we have shown that critical DLL1/4-mediated Notch signals are delivered to donor T cells during a short 48-hour window after transplantation in a mouse allo-BMT model. Stromal, but not hematopoietic, cells were the essential source of Notch ligands during in vivo priming of alloreactive T cells. GVHD could be prevented by selective inactivation of Dll1 and Dll4 in subsets of fibroblastic stromal cells that were derived from chemokine Ccl19-expressing host cells, including fibroblastic reticular cells and follicular dendritic cells. However, neither T cell recruitment into secondary lymphoid organs nor initial T cell activation was affected by Dll1/4 loss. Thus, we have uncovered a pathogenic function for fibroblastic stromal cells in alloimmune reactivity that can be dissociated from their homeostatic functions. Our results reveal what we believe to be a previously unrecognized Notch-mediated immunopathogenic role for stromal cell niches in secondary lymphoid organs after allo-BMT and define a framework of early cellular and molecular interactions that regulate T cell alloimmunity.

논문정보

형식Research article
게재일2017년 03월 (BRIC 등록일 2017-03-27)
연구진국외 연구진
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