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

Jooho Chung, Christen L Ebens, 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 Brennan, D Keith Bishop, Burkhard Ludewig, Christian W Siebel, Freddy Radtke, Sanjiv A Luther & Ivan Maillard

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.
   
citation Chung J, Ebens C L, Perkey E, Radojcic V, Koch U, Scarpellino L, Tong A, Allen F, Wood S, Feng J, Friedman A, Granadier D, Tran I T, Chai Q, Onder L, Yan M, Reddy P, Blazar B R, Huang A Y, Brennan T V, Bishop D K, Ludewig B, Siebel C W, Radtke F, Luther S A, Maillard I. Fibroblastic niches prime T cell alloimmunity through Delta-like Notch ligands. J Clin Invest 2017; 127:1574-1588.
   
type journal paper/review (English)
date of publishing 20-03-2017
journal title J Clin Invest (127/4)
ISSN electronic 1558-8238
pages 1574-1588
PubMed 28319044
DOI 10.1172/JCI89535