Fibroblastic niches prime T cell alloimmunity through Delta-like Notch ligands

Christen L. Ebens, Jooho Chung, Eric Perkey, Vedran Radojcic, Ute Koch, Leonardo Scarpellino, Alexander Tong, Frederick Allen, Sherri Wood, Jiane Feng, Ann Friedman, David Granadier, Ivy T. Tran, Qian Chai, Lucas Onder, Minhong Yan, Pavan Reddy, Bruce R. Blazar, Alex Y. Huang, Todd V. BrennanD. Keith Bishop, Burkhard Ludewig, Christian W. Siebel, Freddy Radtke, Sanjiv A. Luther, Ivan Maillard

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1574-1588
Number of pages15
JournalJournal of Clinical Investigation
Volume127
Issue number4
DOIs
StatePublished - Apr 3 2017

Bibliographical note

Funding Information:
Acknowledgments This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) (R01-AI091627, to IM and R01-AI34495, to BRB); the Leukemia and Lymphoma Society (CDP 1227-14, to IM and TRP 6462-15, to IM and BRB); the Michigan Institute for Clinical and Health Research (to IM); and the Swiss National Science Foundation (to BL, FR, and SAL). Individual support included T32-GM007315 from the National Institute of General Medical Sciences (NIGMS) (to JC), T32-GM007863 from NIGMS (to JC and EP), and T32-HL007762 from the National Heart, Lung, and Blood Institute (to CLE); a research training award from the American Society of Hematology (to VR); and a Career Development Award from the American Society for Blood and Marrow Transplantation (to VR). We thank H.R. McDonald for providing anti-DLL4 antibodies.

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