TY - JOUR AU - Chung, Jooho AU - Ebens, Christen L. AU - Perkey, Eric AU - Radojcic, Vedran AU - Koch, Ute AU - Scarpellino, Leonardo AU - Tong, Alexander AU - Allen, Frederick AU - Wood, Sherri AU - Feng, Jiane AU - Friedman, Ann AU - Granadier, David AU - Tran, Ivy T. AU - Chai, Qian AU - Onder, Lucas AU - Yan, Minhong AU - Reddy, Pavan AU - Blazar, Bruce R. AU - Huang, Alex Y. AU - Brennan, Todd V. AU - Bishop, D. Keith AU - Ludewig, Burkhard AU - Siebel, Christian W. AU - Radtke, Freddy AU - Luther, Sanjiv A. AU - Maillard, Ivan T1 - Fibroblastic niches prime T cell alloimmunity through Delta-like Notch ligands PY - 2017/04/03/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI89535 VL - 127 IS - 4 UR - https://doi.org/10.1172/JCI89535 SP - 1574 EP - 1588 PB - The American Society for Clinical Investigation ER -