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Fibroblastic niches prime T cell alloimmunity through Delta-like Notch ligands
Jooho Chung, … , Sanjiv A. Luther, Ivan Maillard
Jooho Chung, … , Sanjiv A. Luther, Ivan Maillard
Published March 20, 2017
Citation Information: J Clin Invest. 2017;127(4):1574-1588. https://doi.org/10.1172/JCI89535.
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Research Article Hematology Immunology

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

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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.

Authors

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

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Figure 2

Host hematopoietic cells are dispensable as cellular sources of DLL1/4 Notch ligands in acute GVHD.

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Host hematopoietic cells are dispensable as cellular sources of DLL1/4 N...
(A) Experimental strategy. BM chimeras were generated via transplantation of syngeneic B6-CD45.2+ poly(I:C)-induced TgMx1-Cre– littermate control or TgMx1-Cre+ Dll1Δ/Δ Dll4Δ/Δ BM into irradiated B6-CD45.1 recipients. After reestablishment of steady-state hematopoiesis 12 weeks later, BM chimeras were subjected to a second syngeneic or allogeneic transplant, with or without systemic anti-DLL1/4 blockade. (B) Quantification of Dll1 and Dll4 inactivation in sort-purified Gr1+CD11b+ blood myeloid cells from BM chimeras 12 weeks after transplantation (PCR). In this particular experiment, control BM chimeras were generated from poly(I:C)-induced TgMx1-Cre– Dll1fl/+ Dll4fl/+ donor mice. Each lane represents an individual mouse. (C) Donor chimerism (frequency of CD45.2+ donor cells) in the indicated splenic cell populations 12 weeks after transplantation. MΦ, macrophages; pDCs, plasmacytoid DCs. (D) Survival and weight loss of lethally irradiated (11 Gy) BM chimeras transplanted with 8 × 106 TCD BM plus 30 × 106 B6 splenocytes (syngeneic control) or 30 × 106 allogeneic BALB/c splenocytes (allo-BMT). Isotype control or anti-DLL1/4 antibodies were injected i.p. on days 0, 3, 7, and 10 (n = 10 mice/group). (E) Abundance of Dtx1 Notch target gene transcripts (qRT-PCR) in sort-purified donor CD4+ T cells and CD8+ cells on day 6 (n = 5 mice/group). *P < 0.05, **P < 0.01, and NS = P > 0.05, by unpaired, 2-tailed Student’s t test with Sidak’s correction for multiple comparisons. Data are representative of at least 2 experiments; error bars indicate SD.
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