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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 3

Ccl19-Cre+ lineage–traced stromal cells are the critical cellular source of DLL1/4 Notch ligands during acute GVHD.

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Ccl19-Cre+ lineage–traced stromal cells are the critical cellular sourc...
(A) LNs were collected on day 1.5 after transplantation from lethally irradiated TgCcl19-Cre+ ROSA26eYFP mice receiving allogeneic BALB/c splenocytes and enzymatically digested. (A, top) eYFP expression in LN-resident bulk fibroblastic stromal cells (PDPN+CD31–) as well as subfractionated CD157+ FRCs, CD157– FRCs, and CD21+ FDCs. (A, middle) eYFP in LECs, BECs, PDPN–CD31– stromal cells (DNs). (A, bottom) eYFP in macrophages, conventional DCs (cDCs), pDCs, and skin-derived Langerhans cells. Bars in histograms define gating for eYFP+ cells, and numbers indicate the percentage of gated eYFP+ cells within parental cell populations, as identified by flow cytometric analysis. Bar graph in A shows the mean percentage of eYFP expression in each indicated nonhematopoietic subset (n = 4 mice/group; error bars indicate SD). (B) Survival, GVHD score, and weight of lethally irradiated (12 Gy) littermate control TgCcl19-Cre– or TgCcl19-Cre+ Dll1Δ/Δ Dll4Δ/Δ mice that were transplanted with 10 × 106 TCD BM only or 10 × 106 TCD BM plus 20 × 106 allogeneic BALB/c splenocytes. Isotype control or anti-DLL1/4–neutralizing antibodies were injected i.p. on days 0, 3, 7, and 10 (n = 10 mice/group). (C) Intracellular cytokines in donor CD4+ cells after anti-CD3/CD28 restimulation on day 6 (n = 5 mice/group). (D) Relative abundance of Dtx1 and Hes1 Notch target gene transcripts in donor CD4+ T cells sort purified from TgCcl19-Cre– plus isotype control, TgCcl19-Cre– plus anti-DLL1/4, or TgCcl19-Cre+ Dll1Δ/Δ Dll4Δ/Δ recipient mice on day 2 after transplantation (n = 5 mice/group). *P < 0.05, **P < 0.01, and ***P < 0.001, by unpaired, 2-tailed Student’s t test with Sidak’s correction for multiple comparisons. Data are representative of at least 5 experiments; error bars indicate SD.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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