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
|
additional links & downloads
