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

Details

Ressource 1Download: JCI89535.pdf (5176.61 [Ko])
State: Public
Version: Final published version
Serval ID
serval:BIB_7C9AA9DC3589
Type
Article: article from journal or magazin.
Collection
Publications
Title
Fibroblastic niches prime T cell alloimmunity through Delta-like Notch ligands.
Journal
Journal of Clinical Investigation
Author(s)
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.
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Publication state
Published
Issued date
2017
Peer-reviewed
Oui
Volume
127
Number
4
Pages
1574-1588
Language
english
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.

Pubmed
Web of science
Open Access
Yes
Create date
17/04/2017 17:20
Last modification date
20/08/2019 15:38
Usage data