Fibroblastic niches prime T cell alloimmunity through Delta-like Notch ligands.
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.
Jooho
J
Chung
Christen L
CL
Ebens
Eric
E
Perkey
Vedran
V
Radojcic
Ute
U
Koch
Leonardo
L
Scarpellino
Alexander
A
Tong
Frederick
F
Allen
Sherri
S
Wood
Jiane
J
Feng
Ann
A
Friedman
David
D
Granadier
Ivy T
IT
Tran
Qian
Q
Chai
Lucas
L
Onder
Minhong
M
Yan
Pavan
P
Reddy
Bruce R
BR
Blazar
Alex Y
AY
Huang
Todd V
TV
Brennan
D Keith
DK
Bishop
Burkhard
B
Ludewig
Christian W
CW
Siebel
Freddy
F
Radtke
Sanjiv A
SA
Luther
Ivan
I
Maillard
D064591:Allografts; D000818:Animals; D016026:Bone Marrow Transplantation; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology*; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D051880:Receptors, Notch