Notch Signaling in Graft-Versus-Host Disease

  • Lisa M. Minter


Graft-versus-host disease (GVHD) refers to a constellation of adverse immune responses resulting in tissue destruction following hematopoietic stem cell or solid organ transplantation. Through a complex network of priming and activation events, immune-competent T cells residing in the transplanted tissue (the graft) become stimulated, migrate into target organs, and mediate immune destruction of the recipient’s healthy tissue (the host). Paradoxically, this immune activation can also eradicate residual leukemic cells, when hematopoietic stem cell transplantation occurs in the context of hematological malignancies, resulting in a beneficial graft-versus-leukemia (GVL) effect. The Notch family of transmembrane receptors functions in many aspects of immune responses, including those that mediate GVHD. Here we will review the complex nature of GVHD and how Notch signaling may play a prominent role during the initiation and progression of the disease.


Notch Graft-versus-host disease GVHD Graft-versus-leukemia GVL Immune destruction Hematopoietic stem cell transplantation Dll4 M1 macrophages Chemokine receptors Toll-like receptors 


  1. 1.
    Adler, S. H., Chiffoleau, E., Xu, L., Dalton, N. M., Burg, J. M., Wells, A. D., Wolfe, M. S., Turka, L. A., & Pear, W. S. (2003). Notch signaling augments T cell responsiveness by enhancing CD25 expression. Journal of Immunology, 171, 2896–2903.CrossRefGoogle Scholar
  2. 2.
    Alexander, K. A., Flynn, R., Lineburg, K. E., Kuns, R. D., Teal, B. E., Olver, S. D., Lor, M., Raffelt, N. C., Koyama, M., Leveque, L., Le Texier, L., Melino, M., Markey, K. A., Varelias, A., Engwerda, C., Serody, J. S., Janela, B., Ginhoux, F., Clouston, A. D., Blazar, B. R., Hill, G. R., & MacDonald, K. P. (2014). CSF-1- dependant donor-derived macrophages mediate chronic graft-versus-host disease. The Journal of Clinical Investigation, 124, 4266–4280. Scholar
  3. 3.
    Amsen, D., Blander, J. M., Lee, G. R., Tanigaki, K., Honjo, T., & Flavell, R. A. (2004). Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell, 117, 515–526.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Amsen, D., Antov, A., Jankovic, D., Sher, A., Radtke, F., Souabni, A., Busslinger, M., McCright, B., Gridley, T., & Flavell, R. A. (2007). Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity, 27, 89–99.CrossRefGoogle Scholar
  5. 5.
    Amsen, D., Spilianakis, C. G., & Flavell, R. A. (2009). How are T(H)1 and T(H)2 effector cells made? Current Opinion in Immunology, 21, 153–160. Scholar
  6. 6.
    Amsen, D., Helbig, C., & Backer, R. A. (2015). Notch in T cell differentiation: All things considered. Trends in Immunology, 36, 802–814. Scholar
  7. 7.
    Aoyama, K., Saha, A., Tolar, J., Riddle, M. J., Veenstra, R. G., Taylor, P. A., Blomhoff, R., Panoskaltsis Mortari, A., Klebanoff, C. A., Socié, G., Munn, D. H., Murphy, W. J., Serody, J. S., Fulton, L. M., Teshima, T., Chandraratna, R. A., Dmitrovsky, E., Guo, Y., Noelle, R. J., & Blazar, B. R. (2013). Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration. Blood, 122, 2125–2134. Scholar
  8. 8.
    Aster, J. C. (2014). In brief: Notch signalling in health and disease. The Journal of Pathology, 232, 1–3. Scholar
  9. 9.
    Auderset, F., Schuster, S., Coutaz, M., Koch, U., Desgranges, F., Merck, E., MacDonald, H. R., Radtke, F., & Tacchini-Cottier, F. (2012). Redundant Notch1 and Notch2 signaling is necessary for IFNγ secretion by T helper 1 cells during infection with Leishmania major. PLoS Pathogens, 8, e1002560. Scholar
  10. 10.
    Ayaz, F., & Osborne, B. A. (2014). Non-canonical notch signaling in cancer and immunity. Frontiers in Oncology, 4, 345. Scholar
  11. 11.
    Bailis, W., Yashiro-Ohtani, Y., Fang, T. C., Hatton, R. D., Weaver, C. T., Artis, D., & Pear, W. S. (2013). Notch simultaneously orchestrates multiple helper T cell programs independently of cytokine signals. Immunity, 39, 148–159. Scholar
  12. 12.
    Barbarulo, A., Grazioli, P., Campese, A. F., Bellavia, D., Di Mario, G., Pelullo, M., Ciuffetta, A., Colantoni, S., Vacca, A., Frati, L., Gulino, A., Felli, M. P., & Screpanti, I. (2011). Notch3 and canonical NF- kappaB signaling pathways cooperatively regulate Foxp3 transcription. Journal of Immunology, 186, 6199–6206. Scholar
  13. 13.
    Bigas, A., Guiu, J., & Gama-Norton, L. (2013). Notch and Wnt signaling in the emergence of hematopoietic stem cells. Blood Cells, Molecules & Diseases, 51, 264–270. Scholar
  14. 14.
    Beres, A., Komorowski, R., Mihara, M., & Drobyski, W. R. (2011). Instability of FOXP3 expression limits the ability of induced regulatory T cells to mitigate graft versus host disease. Clinical Cancer Research, 17, 3969–3983. Scholar
  15. 15.
    Boonyatecha, N., Sangphech, N., Wongchana, W., Kueanjinda, P., & Palaga, T. (2012). Involvement of Notch signaling pathway in regulating IL-12 expression via c-Rel in activated macrophages. Molecular Immunology, 51, 255–262. Scholar
  16. 16.
    Brennan, T. V., Lin, L., Huang, X., Cardona, D. M., Li, Z., Dredge, K., Chao, N. J., & Yang, Y. (2012). Heparan sulfate, an endogenous TLR4 agonist, promotes acute GVHD after allogeneic stem cell transplantation. Blood, 120, 2899–2908. Scholar
  17. 17.
    Broady, R., Yu, J., Chow, V., Tantiworawit, A., Kang, C., Berg, K., Martinka, M., Ghoreishi, M., Dutz, J., & Levings, M. K. (2010). Cutaneous GVHD is associated with the expansion of tissue-localized Th1 and not Th17 cells. Blood, 116, 5748–5751. Scholar
  18. 18.
    Brown, C. C., Esterhazy, D., Sarde, A., London, M., Pullabhatla, V., Osma-Garcia, I., Al-Bader, R., Ortiz, C., Elgueta, R., Arno, M., de Rinaldis, E., Mucida, D., Lord, G. M., & Noelle, R. J. (2015). Retinoic acid is essential for Th1 cell lineage stability and prevents transition to a Th17 cell program. Immunity, 42, 499–511. Scholar
  19. 19.
    Brunstein, C. G., Miller, J. S., McKenna, D. H., Hippen, K. L., DeFor, T. E., Sumstad, D., Curtsinger, J., Verneris, M. R., ML, M. M., Levine, B. L., Riley, J. I., June, C. H., Le, C., Weisdorf, D., McGlave, P. B., Blazar, B. R., & Wagner, J. E. (2015). Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile and clinical effect. Journal of Immunology, 195, 347–355. Scholar
  20. 20.
    Campese, A. F., Grazioli, P., Colantoni, S., Anastasi, E., Mecarozzi, M., Checquolo, S., De Luca, G., Bellavia, D., Frati, L., Gulino, A., & Screpanti, I. (2009). Notch3 and pTalpha/pre-TCR sustain the in vivo function of naturally occurring regulatory T cells. International Immunology, 21, 727–743. Scholar
  21. 21.
    Charbonnier, L. M., Wang, S., Georgiev, P., Sefik, E., & Chatila, T. A. (2015). Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling. Nature Immunology, 16, 1162–1173. Scholar
  22. 22.
    Cheng, H., Tian, J., Li, Z., Zeng, L., Pan, B., Song, G., Chen, W., & Xu, K. (2012). TH17 cells are critical for skin-specific pathological injury in acute graft-versus-host disease. Transplantation Proceedings, 44, 1412–1418. Scholar
  23. 23.
    Cheng, H., Tian, J., Zeng, L., Pan, B., Li, Z., Song, G., Chen, W., & Xu, K. (2012). Halofugine prevents cutaneous graft versus host disease by suppression of Th17 differentiation. Hematology, 17, 261–267. Scholar
  24. 24.
    Christian, L. M. (2012). The ADAM family: Insights into Notch proteolysis. Fly (Austin)., 6, 30–34. Scholar
  25. 25.
    Demitrack, E. S., & Samuelson, L. C. (2016). Notch regulation of gastrointestinal stem cells. The Journal of Physiology, 594, 4791–4803. Scholar
  26. 26.
    Dietz, A. C., Lucchini, G., Samarasinghe, S., & Pulsipher, M. A. (2016). Evolving hematopoietic stem cell transplantation strategies in severe aplastic anemia. Current Opinion in Pediatrics, 28, 3–11. Scholar
  27. 27.
    Duggan, S. P., & McCarthy, J. V. (2016). Beyond γ-secretase activity: The multifunctional nature of presenilins in cell signalling pathways. Cellular Signalling, 28, 1–11. Scholar
  28. 28.
    Duffner, U. A., Maeda, Y., Cooke, K. R., Reddy, P., Ordemann, R., Liu, C., Ferrara, J. L., & Teshima, T. (2004). Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease. Journal of Immunology, 172, 7393–7398.CrossRefGoogle Scholar
  29. 29.
    Dongre, A., Surampudi, L., Lawlor, R. G., Fauq, A. H., Miele, L., Golde, T. E., Minter, L. M., & Osborne, B. A. (2014). Non-canonical Notch signaling drives activation and differentiation of peripheral CD4(+) T cells. Frontiers in Immunology, 5, 54. Scholar
  30. 30.
    Ebens, C. L., & Maillard, I. (2013). Notch signaling in hematopoietic cell transplantation and T cell alloimmunity. Blood Reviews, 27, 269–277. Scholar
  31. 31.
    Ehebauer, M., Hayward, P., & Martinez-Arias, A. (2006). Notch signaling pathway. Science’s STKE, 2006(364), cm7.PubMedGoogle Scholar
  32. 32.
    Fang, T. C., Yashiro-Ohtani, Y., Del Bianco, C., Knoblock, D. M., Blacklow, S. C., & Pear, W. S. (2007). Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity, 27, 100–110.CrossRefGoogle Scholar
  33. 33.
    Fu, J., Wang, D., Yu, Y., Heinrichs, J., Wu, Y., Schutt, S., Kaosaard, K., Liu, C., Haarberg, K., Bastian, D., McDonald, D. G., Anasetti, C., & Yu, X. Z. (2015). T-bet is critical for the development of acute graft- versus-host disease through controlling T cell differentiation and function. Journal of Immunology, 194, 388–397. Scholar
  34. 34.
    Fung, E., Tang, S. M., Canner, J. P., Morishige, K., Arboleda-Velasquez, J. F., Cardoso, A. A., Carlesso, N., Aster, J. C., & Aikawa, M. (2007). Delta-like 4 induces notch signaling in macrophages: Implications for inflammation. Circulation, 115, 2948–2956.CrossRefGoogle Scholar
  35. 35.
    Gowdy, K. M., Nugent, J. L., Martinu, T., Potts, E., Snyder, L. D., Foster, W. M., & Palmer, S. M. (2011). Protective role of T-bet and Th1 cytokines in pulmonary graft-versus-host disease and peribronchiolar fibrosis. American Journal of Respiratory Cell and Molecular Biology, 46, 249–256. Scholar
  36. 36.
    Hadeiba, H., Sato, T., Habtezion, A., Oderup, C., Pan, J., & Butcher, E. C. (2008). CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nature Immunology, 9, 1253–1260. Scholar
  37. 37.
    Harbour, S. N., Maynard, C. L., Zindl, C. L., Schoeb, T. R., & Weaver, C. T. (2015). Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proceedings of the National Academy of Sciences of the United States of America, 112, 7061–7066. Scholar
  38. 38.
    Hashimoto, D., Chow, A., Greter, M., Saenger, Y., Kwan, W. H., Leboeuf, M., Ginhoux, F., Ochando, J. C., Kunisaki, Y., van Rooijen, N., Liu, C., Teshima, T., Heeger, P. S., Stanley, E. R., Frenette, P. S., & Merad, M. (2011). Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation. The Journal of Experimental Medicine, 208, 1069–1082. Scholar
  39. 39.
    Hayashida, J. N., Nakamura, S., Toyoshima, T., Moriyama, M., Sasaki, M., Kawamura, E., Ohyama, Y., Kumamaru, W., & Shirasuna, K. (2013). Possible involvement of cytokines, chemokines and chemokine receptors in the initiation and progression of chronic GVHD. Bone Marrow Transplantation, 48, 115–123. Scholar
  40. 40.
    He, S., Cao, Q., Qiu, Y., Mi, J., Zhang, J. Z., Jin, M., Ge, H., Emerson, S. G., Zhang, Y., & Zhang, Y. (2008). A new approach to the blocking of alloreactive T cell-mediated graft-versus-host disease by in vivo administration of anti-CXCR3 neutralizing antibody. Journal of Immunology, 181, 7581–7592.CrossRefGoogle Scholar
  41. 41.
    Heidegger, S., van den Brink, M. R., Haas, T., & Poeck, H. (2014). The role of pattern-recognition receptors in graft-versus-host disease and graft-versus-leukemia after allogeneic stem cell transplantation. Frontiers in Immunology, 5, 337. Scholar
  42. 42.
    Hill, G. R., Crawford, J. M., Cooke, K. R., Brinson, Y. S., Pan, L., & Ferrara, J. L. (1997). Total body irradiation and acute graft-versus-host disease: The role of gastrointestinal damage and inflammatory cytokines. Blood, 90, 3204–3213.PubMedGoogle Scholar
  43. 43.
    Holler, E., Landfried, K., Meier, J., Hausmann, M., & Rogler, G. (2013). The role of bacteria and pattern recognition receptors in GVHD. International Journal of Inflammation, 2010, 814326. Scholar
  44. 44.
    Hoyne, G. F., Le Roux, I., Corsin-Jimenez, M., Tan, K., Dunne, J., Forsyth, L. M., Dallman, M. J., Owen, M. J., Ish-Horowicz, D., & Lamb, J. R. (2000). Serrate1-induced notch signalling regulates the decision between immunity and tolerance made by peripheral CD4(+) T cells. International Immunology, 12, 177–185.CrossRefGoogle Scholar
  45. 45.
    Hu, X., Chung, A. Y., Wu, I., Foldi, J., Chen, J., Ji, J. D., Tateya, T., Kang, Y. J., Han, J., Gessler, M., Kageyama, R., & Ivashkiv, L. B. (2008). Integrated regulation of Toll-like receptor responses by Notch and interferon-gamma pathways. Immunity, 29, 691–703. Scholar
  46. 46.
    Hue, S., Kared, H., Mehwish, Y., Mouhamad, S., Balbo, M., & Levy, Y. (2012). Notch activation on effector T cells increases their sensitivity to Treg cell-mediated suppression through upregulation of TGF-βRII expression. European Journal of Immunology, 42, 1796–1803. Scholar
  47. 47.
    Iclozan, C., Yu, Y., Liu, C., Liang, Y., Yi, T., Anasetti, C., & Yu, X. Z. (2009). T helper17 cells are sufficient but not necessary to induce acute graft-versus-host disease. Biology of Blood and Marrow Transplantation, 16, 170–178. Scholar
  48. 48.
    Imanguli, M. M., Swaim, W. D., League, S. C., Gress, R. E., Pavletic, S. Z., & Hakim, F. T. (2009). Increased T- bet+ cytotoxic effectors and type I interferon-mediated processes in chronic graft-versus-host disease of the oral mucosa. Blood, 113, 3620–3630. Scholar
  49. 49.
    Ju, J. M., Lee, H., Oh, K., Lee, D. S., & Choi, E. Y. (2014). Kinetics of IFN-γ and IL-17 production by CD4 and CD8 T cells during acute graft-versus-host disease. Immune Network, 14, 89–99. Scholar
  50. 50.
    Kassner, N., Krueger, M., Yagita, H., Dzionek, A., Hutloff, A., Kroczek, R., Scheffold, A., & Rutz, S. (2010). Cutting edge: Plasmacytoid dendritic cells induce IL-10 production in T cells via the Delta-like-4/Notch axis. Journal of Immunology, 184, 550–554. Scholar
  51. 51.
    Kimura, A., Naka, T., & Kishimoto, T. (2007). IL-6-dependent and -independent pathways in the development of interleukin 17-producing T helper cells. Proceedings of the National Academy of Sciences of the United States of America, 104, 12099–12104.CrossRefGoogle Scholar
  52. 52.
    Koch, M. A., Tucker-Heard, G., Perdue, N. R., Killebrew, J. R., Urdahl, K. B., & Campbell, D. J. (2009). The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nature Immunology, 10, 595–602. Scholar
  53. 53.
    Koch, U., & Radtke, F. (2011). Mechanisms of T cell development and transformation. Annual Review of Cell and Developmental Biology, 27, 539–562. Scholar
  54. 54.
    Komatsu, N., Okamoto, K., Sawa, S., Nakashima, T., Oh-hora, M., Kodama, T., Tanaka, S., Bluestone, J. A., & Takayanagi, H. (2014). Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nature Medicine, 20, 62–68. Scholar
  55. 55.
    Kotsiou, E., & Davies, J. K. (2013). New ways to separate graft-versus-host disease and graft-versus- tumour effects after allogeneic haematopoietic stem cell transplantation. British Journal of Haematology, 160, 133–145. Scholar
  56. 56.
    Kovall, R. A. (2007). Structures of CSL, Notch and Mastermind proteins: Piecing together an active transcription complex. Current Opinion in Structural Biology, 17, 117–127.CrossRefGoogle Scholar
  57. 57.
    Koyama, M., Cheong, M., Markey, K. A., Gartlan, K. H., Kuns, R. D., Locke, K. R., Lineburg, K. E., Teal, B. E., Leveque-El Mouttie, L., Bunting, M. D., Vuckovic, S., Zhang, P., Teng, M. W., Varelias, A., Tey, S. K., Wockner, L. F., Engwerda, C. R., Smyth, M. J., Belz, G. T., McColl, S. R., MacDonald, K. P., & Hill, G. R. (2015). Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease. The Journal of Experimental Medicine, 212, 1303–1321. Scholar
  58. 58.
    Koyama, M., Hashimoto, D., Aoyama, K., Matsuoka, K., Karube, K., Niiro, H., Harada, M., Tanimoto, M., Akashi, K., & Teshima, T. (2009). Plasmacytoid dendritic cells prime alloreactive T cells to mediate graft-versus-host disease as antigen-presenting cells. Blood, 113, 2088–2095. Scholar
  59. 59.
    Kryczek, I., Zhao, E., Liu, Y., Wang, Y., Vatan, L., Szeliga, W., Moyer, J., Klimczak, A., Lange, A., & Zou, W. (2011). Human TH17 cells are long-lived effector memory cells. Science Translational Medicine, 3, 104ra100. Scholar
  60. 60.
    Lai, H. Y., Chou, T. Y., Tzeng, C. H., & Lee, O. K. (2012). Cytokine profiles in various graft-versus- host disease target organs following hematopoietic stem cell transplantation. Cell Transplantation, 21, 2033–2045. Scholar
  61. 61.
    Laky, K., & Fowlkes, B. J. (2008). Notch signaling in CD4 and CD8 T cell development. Current Opinion in Immunology, 20, 197–202. Scholar
  62. 62.
    Li, C. R., Mueller, E. E., & Bradley, L. M. (2014). Islet antigen-specific Th17 cells can induce TNF-α- dependent autoimmune diabetes. Journal of Immunology, 192, 1425–1432. Scholar
  63. 63.
    Li, H., Demetris, A. J., McNiff, J., Matte-Martone, C., Tan, H. S., Rothstein, D. M., & Lakkis, F. G. (2012). Shlomchik WD (2012) Profound depletion of host conventional dendritic cells, plasmacytoid dendritic cells, and B cells does not prevent graft-versus-host disease induction. Journal of Immunology, 188(8), 3804–3811. Scholar
  64. 64.
    Li, J. M., Giver, C. R., Lu, Y., Hossain, M. S., Akhtari, M., & Waller, E. K. (2009). Separating graft-versus- leukemia from graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. Immunotherapy, 1, 599–621.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Li, N., Chen, Y., He, W., Yi, T., Zhao, D., Zhang, C., Lin, C. L., Todorov, I., Kandeel, F., Forman, S., & Zeng, D. (2009). Anti-CD3 preconditioning separates GVL from GVHD via modulating host dendritic cell and donor T-cell migration in recipients conditioned with TBI. Blood, 113, 953–962. Scholar
  66. 66.
    Li, S., Xie, Q., Zeng, Y., Zou, C., Liu, X., Wu, S., Deng, H., Xu, Y., Li, X. C., & Dai, Z. (2014). A naturally occurring CD8(+)CD122(+) T-cell subset as a memory-like Treg family. Cellular & Molecular Immunology, 11, 326–331. Scholar
  67. 67.
    Lin, X., Lu, Z. G., Song, C. Y., Huang, Y. X., Guo, K. Y., Deng, L., Tu, S. F., He, Y. Z., Xu, J. H., Long, H., & Wu, B. Y. (2015). Long-term outcome of HLA-haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion based on an FBCA conditioning regimen for hematologic malignancies. Bone Marrow Transplantation, 50, 1092–1097. Scholar
  68. 68.
    Liotta, F., Frosali, F., Querci, V., Mantei, A., Filì, L., Maggi, L., Mazzinghi, B., Angeli, R., Ronconi, E., Santarlasci, V., Biagioli, T., Lasagni, L., Ballerini, C., Parronchi, P., Scheffold, A., Cosmi, L., Maggi, E., Romagnani, S., & Annunziato, F. (2008). Human immature myeloid dendritic cells trigger a TH2- polarizing program via Jagged-1/Notch interaction. The Journal of Allergy and Clinical Immunology, 121, 1000–1005.e8. Scholar
  69. 69.
    Liu, H. P., Cao, A. T., Feng, T., Li, Q., Zhang, W., Yao, S., Dann, S. M., Elson, C. O., & Cong, Y. (2015). TGF-β converts Th1 cells into Th17 cells through stimulation of Runx1 expression. European Journal of Immunology, 45, 1010–1018. Scholar
  70. 70.
    Maillard, I., Weng, A. P., Carpenter, A. C., Rodriguez, C. G., Sai, H., Xu, L., Allman, D., Aster, J. C., & Pear, W. S. (2004). Mastermind critically regulates Notch-mediated lymphoid cell fate decisions. Blood, 104, 1696–1702.CrossRefGoogle Scholar
  71. 71.
    Mangan, P. R., Harrington, L. E., O’Quinn, D. B., Helms, W. S., Bullard, D. C., Elson, C. O., Hatton, R. D., Wahl, S. M., Schoeb, T. R., & Weaver, C. T. (2006). Transforming growth factor-beta induces development of the T(H)17 lineage. Nature, 441, 231–234.CrossRefGoogle Scholar
  72. 72.
    Mapara, M. Y., Leng, C., Kim, Y. M., Bronson, R., Lokshin, A., Luster, A., & Sykes, M. (2006). Expression of chemokines in GVHD target organs is influenced by conditioning and genetic factors and amplified by GVHR. Biology of Blood and Marrow Transplantation, 12, 623–634.CrossRefGoogle Scholar
  73. 73.
    Martinez Arias, A., Zecchini, V., & Brennan, K. (2002). CSL-independent Notch signalling: A checkpoint in cell fate decisions during development? Current Opinion in Genetics & Development, 12, 524–533.CrossRefGoogle Scholar
  74. 74.
    Mauermann, N., Burian, J., von Garnier, C., Dirnhofer, S., Germano, D., Schuett, C., Tamm, M., Bingisser, R., Eriksson, U., & Hunziker, L. (2008). Interferon-gamma regulates idiopathic pneumonia syndrome, a Th17+CD4+ T-cell-mediated graft-versus-host disease. American Journal of Respiratory and Critical Care Medicine, 178, 379–388. Scholar
  75. 75.
    Meng, L., Bai, Z., He, S., Mochizuki, K., Liu, Y., Purushe, J., Sun, H., Wang, J., Yagita, H., Mineishi, S., Fung, H., Yanik, G. A., Caricchio, R., Fan, X., Crisalli, L. M., Hexner, E. O., Reshef, R., Zhang, Y., & Zhang, Y. (2016). The Notch ligand DLL4 defines a capability of human dendritic cells in regulating Th1 and Th17 differentiation. Journal of Immunology, 196(3), 1070–1080. Epub 2015 Dec 28.CrossRefGoogle Scholar
  76. 76.
    Michael, M., Shimoni, A., & Nagler, A. (2013). Regulatory T cells in allogeneic stem cell transplantation. Clinical & Developmental Immunology, 2013, 608951. Scholar
  77. 77.
    Minter, L. M., Turley, D. M., Das, P., Shin, H. M., Joshi, I., Lawlor, R. G., Cho, O. H., Palaga, T., Gottipati, S., Telfer, J. C., Kostura, L., Fauq, A. H., Simpson, K., Such, K. A., Miele, L., Golde, T. E., Miller, S. D., & Osborne, B. A. (2005). Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. Nature Immunology, 6, 680–688.CrossRefGoogle Scholar
  78. 78.
    Minter, L. M., & Osborne, B. A. (2012). Canonical and non-canonical Notch signaling in CD4+ T cells. Current Topics in Microbiology and Immunology, 360, 99–114. Scholar
  79. 79.
    Mirandola, L., Chiriva-Internati, M., Montagna, D., Locatelli, F., Zecca, M., Ranzani, M., Basile, A., Locati, M., Cobos, E., Kast, W. M., Asselta, R., Paraboschi, E. M., Comi, P., & Chiaramonte, R. (2012). Notch1 regulates chemotaxis and proliferation by controlling the CC-chemokine receptors 5 and 9 in T cell acute lymphoblastic leukaemia. The Journal of Pathology, 226, 713–722. Scholar
  80. 80.
    Mochizuki, K., He, S., & Zhang, Y. (2011). Notch and inflammatory T-cell response: New developments and challenges. Immunotherapy, 3, 1353–1366. Scholar
  81. 81.
    Mochizuki, K., Xie, F., He, S., Tong, Q., Liu, Y., Mochizuki, I., Guo, Y., Kato, K., Yagita, H., Mineishi, S., & Zhang, Y. (2013). Delta-like ligand 4 identifies a previously uncharacterized population of inflammatory dendritic cells that plays important roles in eliciting allogeneic T cell responses in mice. Journal of Immunology, 190, 3772–3782. Scholar
  82. 82.
    Monsalve, E., Pérez, M. A., Rubio, A., Ruiz-Hidalgo, M. J., Baladrón, V., García-Ramírez, J. J., Gómez, J. C., Laborda, J., & Díaz-Guerra, M. J. (2006). Notch-1 up-regulation and signaling following macrophage activation modulates gene expression patterns known to affect antigen-presenting capacity and cytotoxic activity. Journal of Immunology, 176, 5362–5373.CrossRefGoogle Scholar
  83. 83.
    Morikawa, H., & Sakaguchi, S. (2014). Genetic and epigenetic basis of Treg cell development and function: From a FoxP3-centered view to an epigenome-defined view of natural Treg cells. Immunological Reviews, 259, 192–205. Scholar
  84. 84.
    Mota, C., Nunes-Silva, V., Pires, A. R., Matoso, P., Victorino, R. M., Sousa, A. E., & Caramalho, I. (2014). Delta-like 1-mediated Notch signaling enhances the in vitro conversion of human memory CD4 T cells intoFOXP3-expressing regulatory T cells. Journal of Immunology, 193, 5854–5862. Scholar
  85. 85.
    Mukherjee, S., Schaller, M. A., Neupane, R., Kunkel, S. L., & Lukacs, N. W. (2009). Regulation of T cell activation by Notch ligand, DLL4, promotes IL-17 production and Rorc activation. Journal of Immunology, 182, 7381–7388. Scholar
  86. 86.
    Nishiwaki, S., Terakura, S., Ito, M., Goto, T., Seto, A., Watanabe, K., Yanagisawa, M., Imahashi, N., Tsukamoto, S., Shimba, M., Ozawa, Y., & Miyamura, K. (2009). Impact of macrophage infiltration of skin lesions on survival after allogeneic stem cell transplantation: A clue to refractory graft- versus-host disease. Blood, 114, 3113–3116. Scholar
  87. 87.
    Nishiwaki, S., Nakayama, T., Murata, M., Nishida, T., Terakura, S., Saito, S., Kato, T., Mizuno, H., Imahashi, N., Seto, A., Ozawa, Y., Miyamura, K., Ito, M., Takeshita, K., Kato, H., Toyokuni, S., Nagao, K., Ueda, R., & Naoe, T. (2014). Dexamethasone palmitate ameliorates macrophages-rich graft-versus- host disease by inhibiting macrophage functions. PLoS One, 9, e96252. Scholar
  88. 88.
    Osborne, B. A., & Minter, L. M. (2007). Notch signalling during peripheral T-cell activation and differentiation. Nature Reviews. Immunology, 7, 64–75.CrossRefGoogle Scholar
  89. 89.
    Ostroukhova, M., Qi, Z., Oriss, T. B., Dixon-McCarthy, B., Ray, P., & Ray, A. (2006). Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-beta. The Journal of Clinical Investigation, 116, 996–1004.CrossRefGoogle Scholar
  90. 90.
    Ong, C. T., Sedy, J. R., Murphy, K. M., & Kopan, R. (2008). Notch and presenilin regulate cellular expansion and cytokine secretion but cannot instruct Th1/Th2 fate acquisition. PLoS One, 3, e2823. Scholar
  91. 91.
    Ou-Yang, H. F., Zhang, H. W., Wu, C. G., Zhang, P., Zhang, J., Li, J. C., Hou, L. H., He, F., Ti, X. Y., Song, L. Q., Zhang, S. Z., Feng, L., Qi, H. W., & Han, H. (2009). Notch signaling regulates the FOXP3 promoter through RBP-J- and Hes1-dependent mechanisms. Molecular and Cellular Biochemistry, 320, 109–114. Scholar
  92. 92.
    Palaga, T., Miele, L., Golde, T. E., & Osborne, B. A. (2003). TCR-mediated Notch signaling regulates proliferation and IFN-gamma production in peripheral T cells. Journal of Immunology, 171, 3019–3024.CrossRefGoogle Scholar
  93. 93.
    Pan, B., Zhang, Y., Sun, Y., Cheng, H., Wu, Y., Song, G., Chen, W., Zeng, L., & Xu, K. (2014). Deviated balance between Th1 and Th17 cells exacerbates acute graft-versus-host disease in mice. Cytokine, 68, 69–75. Scholar
  94. 94.
    Parmar, S., Liu, X., Tung, S. S., Robinson, S. N., Rodriguez, G., Cooper, L. J., Yang, H., Shah, N., Yang, H., Konopleva, M., Molldrem, J. J., Garcia-Manero, G., Najjar, A., Yvon, E., McNiece, I., Rezvani, K., Savoldo, B., Bollard, C. M., & Shpall, E. J. (2015). Third-party umbilical cord blood-derived regulatory T cells prevent xenogenic graft-versus-host disease. Blood. pii: blood-2015-06-653667. [Epub ahead of print].Google Scholar
  95. 95.
    Pasquini, M. C. (2008). Impact of graft-versus-host disease on survival. Best Practice & Research. Clinical Haematology, 21, 193–204. Scholar
  96. 96.
    Perumalsamy, L. R., Marcel, N., Kulkarni, S., Radtke, F., & Sarin, A. (2012). Distinct spatial and molecular features of notch pathway assembly in regulatory T cells. Science Signaling, 5, ra53. Scholar
  97. 97.
    Pierini, A., Colonna, L., Alvarez, M., Schneidawind, D., Nishikii, H., Baker, J., Pan, Y., Florek, M., Kim, B. S., & Negrin, R. S. (2014). Donor requirements for regulatory T cell suppression of murine graft- versus-host disease. Cytotherapy, 16, 90–100. Scholar
  98. 98.
    Pratt, E. B., Wentzell, J. S., Maxson, J. E., Courter, L., Hazelett, D., & Christian, J. L. (2011). The cell giveth and the cell taketh away: An overview of Notch pathway activation by endocytic trafficking of ligands and receptors. Acta Histochemica, 113, 248–255. Scholar
  99. 99.
    Ratajczak, M. Z., & Suszynska, M. (2016). Emerging strategies to enhance homing and engraftment of hematopoietic stem cells. Stem Cell Reviews, 12, 121–128. Scholar
  100. 100.
    Reshef, R., Luger, S. M., Hexner, E. O., Loren, A. W., Frey, N. V., Nasta, S. D., Goldstein, S. C., Stadtmauer, E. A., Smith, J., Bailey, S., Mick, R., Heitjan, D. F., Emerson, S. G., Hoxie, J. A., Vonderheide, R. H., & Porter, D. L. (2012). Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. The New England Journal of Medicine, 367, 135–145. Scholar
  101. 101.
    Roderick, J. E., Gonzalez-Perez, G., Kuksin, C. A., Dongre, A., Roberts, E. R., Srinivasan, J., Andrzejewski, C., Jr., Fauq, A. H., Golde, T. E., Miele, L., & Minter, L. M. (2013). Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia. The Journal of Experimental Medicine, 210, 1311–1329. Scholar
  102. 102.
    Rutz, S., Janke, M., Kassner, N., Hohnstein, T., Krueger, M., & Scheffold, A. (2008). Notch regulates IL- 10 production by T helper 1 cells. Proceedings of the National Academy of Sciences of the United States of America, 105, 3497–3502. Scholar
  103. 103.
    Samon, J. B., Champhekar, A., Minter, L. M., Telfer, J. C., Miele, L., Fauq, A., Das, P., Golde, T. E., & Osborne, B. A. (2008). Notch1 and TGFbeta1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells. Blood, 112, 1813–1821. Scholar
  104. 104.
    Sandy, A. R., Jones, M., & Maillard, I. (2012). Notch signaling and development of the hematopoietic system. Advances in Experimental Medicine and Biology, 727, 71–88. Scholar
  105. 105.
    Sandy, A. R., Chung, J., Toubai, T., Shan, G. T., Tran, I. T., Friedman, A., Blackwell, T. S., Reddy, P., King, P. D., & Maillard, I. (2013). T cell-specific notch inhibition blocks graft-versus-host disease by inducing a hyporesponsive program in alloreactive CD4+ and CD8+ T cells. Journal of Immunology, 190, 5818–5828. Scholar
  106. 106.
    Schmitt, E. G., & Williams, C. B. (2013). Generation and function of induced regulatory T cells. Frontiers in Immunology, 4, 152. eCollection 2013.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Schmitt, N., & Ueno, H. (2015). Regulation of human helper T cell subset differentiation by cytokines. Current Opinion in Immunology, 34, 130–136. Scholar
  108. 108.
    Schwanbeck, R. (2015). The role of epigenetic mechanisms in Notch signaling during development. Journal of Cellular Physiology, 230, 969–981. Scholar
  109. 109.
    Shlomchik, W. D. (2007). Graft-versus-host disease. Nature Reviews. Immunology, 7, 340–352.CrossRefGoogle Scholar
  110. 110.
    Singla, R. D., Wang, J., & Singla, D. K. (2014). Regulation of Notch 1 signaling in THP-1 cells enhances M2 macrophage differentiation. American Journal of Physiology. Heart and Circulatory Physiology, 307, H1634–H1642. Scholar
  111. 111.
    Skokos, D., & Nussenzweig, M. C. (2007). CD8− DCs induce IL-12–independent Th1 differentiation through Delta 4 Notch-like ligand in response to bacterial LPS. The Journal of Experimental Medicine, 204, 1525–1531. Scholar
  112. 112.
    Szabo, S. J., Kim, S. T., Costa, G. L., Zhang, X., Fathman, C. G., & Glimcher, L. H. (2000). A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell, 100, 655–669.CrossRefGoogle Scholar
  113. 113.
    Theil, A., Tuve, S., Oelschlägel, U., Maiwald, A., Döhler, D., Oßmann, D., Zenkel, A., Wilhelm, C., Middeke, J. M., Shayegi, N., Trautmann-Grill, K., von Bonin, M., Platzbecker, U., Ehninger, G., Bonifacio, E., & Bornhäuser, M. (2015). Adoptive transfer of allogeneic regulatory T cells into patients with chronic graft-versus-host disease. Cytotherapy, 17, 473–486. Scholar
  114. 114.
    Tran, I. T., Sandy, A. R., Carulli, A. J., Ebens, C., Chung, J., Shan, G. T., Radojcic, V., Friedman, A., Gridley, T., Shelton, A., Reddy, P., Samuelson, L. C., Yan, M., Siebel, C. W., & Maillard, I. (2013). Blockade of individual Notch ligands and receptors controls graft-versus-host disease. The Journal of Clinical Investigation, 123, 1590–1604.CrossRefGoogle Scholar
  115. 115.
    Tu, L., Fang, T. C., Artis, D., Shestova, O., Pross, S. E., Maillard, I., & Pear, W. S. (2005). Notch signaling is an important regulator of type 2 immunity. The Journal of Experimental Medicine, 202, 1037–1042.CrossRefGoogle Scholar
  116. 116.
    Ukena, S. N., Grosse, J., Mischak-Weissinger, E., Buchholz, S., Stadler, M., Ganser, A., & Franzke, A. (2011). Acute but not chronic graft-versus-host disease is associated with a reduction of circulating CD4(+)CD25 (high)CD127 (low/-) regulatory T cells. Annals of Hematology, 90, 213–218. (a).CrossRefPubMedGoogle Scholar
  117. 117.
    Ukena, S. N., Velaga, S., Geffers, R., Grosse, J., Baron, U., Buchholz, S., Stadler, M., Bruder, D., Ganser, A., & Franzke, A. (2012). Human regulatory T cells in allogeneic stem cell transplantation. Blood, 118, e82–e92. (b).CrossRefGoogle Scholar
  118. 118.
    van den Brink, M. R., Velardi, E., & Perales, M. A. (2015). Immune reconstitution following stem cell transplantation. Hematology. American Society of Hematology. Education Program, 2015, 215–219. Scholar
  119. 119.
    van der Waart, A. B., van der Velden, W. J., Blijlevens, N. M., & Dolstra, H. (2014). Targeting the IL17 pathway for the prevention of graft-versus-host disease. Biology of Blood and Marrow Transplantation, 20, 752–759. Scholar
  120. 120.
    Varona, R., Cadenas, V., Gómez, L., Martínez-A, C., & Márquez, G. (2005). CCR6 regulates CD4+ T- cell-mediated graft-versus-host disease responses. Blood, 106, 18–26.CrossRefGoogle Scholar
  121. 121.
    Vianello, F., Cannella, L., Coe, D., Chai, J. G., Golshayan, D., Marelli-Berg, F. M., & Dazzi, F. (2013). Enhanced and aberrant T cell trafficking following total body irradiation: a gateway to graft- versus-host disease? British Journal of Haematology, 162, 808–818. Scholar
  122. 122.
    Wang, Y. C., He, F., Feng, F., Liu, X. W., Dong, G. Y., Qin, H. Y., Hu, X. B., Zheng, M. H., Liang, L., Feng, L., Liang, Y. M., & Han, H. (2010). Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Research, 70, 4840–4849. Scholar
  123. 123.
    Wendland, M., Czeloth, N., Mach, N., Malissen, B., Kremmer, E., Pabst, O., & Förster, R. (2007). CCR9 is a homing receptor for plasmacytoid dendritic cells to the small intestine. Proceedings of the National Academy of Sciences of the United States of America, 104, 6347–6352.CrossRefGoogle Scholar
  124. 124.
    Wongchana, W., & Palaga, T. (2012). Direct regulation of interleukin-6 expression by Notch signaling in macrophages. Cellular & Molecular Immunology, 9, 155–162. Scholar
  125. 125.
    Wongchana, W., Lawlor, R. G., Osborne, B. A., & Palaga, T. (2015). Impact of Notch1 deletion in macrophages on proinflammatory cytokine production and the outcome of experimental autoimmune encephalomyelitis. Journal of Immunology, 195, 5337–5346. Scholar
  126. 126.
    Wu, Y., Bastian, D., Schutt, S., Nguyen, H., Fu, J., Heinrichs, J., Xia, C., & Yu, X. Z. (2015). Essential role of interleukin-12/23p40 in the development of graft-versus-host disease in mice. Biology of Blood and Marrow Transplantation, 21, 1195–1204. Scholar
  127. 127.
    Xiao, S., Jin, H., Korn, T., Liu, S. M., Oukka, M., Lim, B., & Kuchroo, V. K. (2008). Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. Journal of Immunology, 181, 2277–2284.CrossRefGoogle Scholar
  128. 128.
    Xu, H., Zhu, J., Smith, S., Foldi, J., Zhao, B., Chung, A. Y., Outtz, H., Kitajewski, J., Shi, C., Weber, S., Saftig, P., Li, Y., Ozato, K., Blobel, C. P., Ivashkiv, L. B., & Hu, X. (2012). Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization. Nature Immunology, 13, 642–650. Scholar
  129. 129.
    Xu, J., Chi, F., Guo, T., Punj, V., Lee, W. N., French, S. W., & Tsukamoto, H. (2015). NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. The Journal of Clinical Investigation, 125, 1579–1590. Scholar
  130. 130.
    Yamane, H., & Paul, W. E. (2013). Early signaling events that underlie fate decisions of naive CD4(+) T cells toward distinct T-helper cell subsets. Immunological Reviews, 252, 12–23. Scholar
  131. 131.
    Yi, T., Chen, Y., Wang, L., Du, G., Huang, D., Zhao, D., Johnston, H., Young, J., Todorov, I., Umetsu, D. T., Chen, L., Iwakura, Y., Kandeel, F., Forman, S., & Zeng, D. (2009). Reciprocal differentiation and tissue- specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease. Blood, 114, 3101–3112. Scholar
  132. 132.
    Yu, Q., Sharma, A., Oh, S. Y., Moon, H. G., Hossain, M. Z., Salay, T. M., Leeds, K. E., Du, H., Wu, B., Waterman, M. L., Zhu, Z., & Sen, J. M. (2009). T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-gamma. Nature Immunology, 10, 992–999. Scholar
  133. 133.
    Yu, Y., Wang, D., Liu, C., Kaosaard, K., Semple, K., Anasetti, C., & Yu, X. Z. (2011). Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORγt in mice. Blood, 118, 5011–5020. Scholar
  134. 134.
    Yuan, J., Ren, H. Y., Shi, Y. J., & Liu, W. (2015). Prophylaxis of acute graft-versus-host disease by CCR5 blockade combined with cyclosporine A in a murine model. Inflammation Research, 64, 137–144. Scholar
  135. 135.
    Zeng, C., Xing, R., Liu, J., & Xing, F. (2016). Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis. Apoptosis, 21, 1–12. [Epub ahead of print].CrossRefGoogle Scholar
  136. 136.
    Zhang, Y., Sandy, A. R., Wang, J., Radojcic, V., Shan, G. T., Tran, I. T., Friedman, A., Kato, K., He, S., Cui, S., Hexner, E., Frank, D. M., Emerson, S. G., Pear, W. S., & Maillard, I. (2011). Notch signaling is a critical regulator of allogeneic CD4+ T-cell responses mediating graft-versus-host disease. Blood, 117, 299–308. Scholar
  137. 137.
    Zhao, Y., Liu, Q., Yang, L., He, D., Wang, L., Tian, J., Li, Y., Zi, F., Bao, H., Yang, Y., Zheng, Y., Shi, J., Xue, X., & Cai, Z. (2013). TLR4 inactivation protects from graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Cellular & Molecular Immunology, 10, 165–175. Scholar
  138. 138.
    Fulton, L. M., Carlson, M. J., Coghill, J. M., Ott, L. E., West, M. L., Panoskaltsis-Mortari, A., Littman, D. R., Blazar, B. R., & Serody, J. S. (2012). Attenuation of Acute Graft-versus-Host Disease in the Absence of the Transcription Factor ROR t. The Journal of Immunology, 189(4):1765–1772. Epub 2012 Jul 9.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Veterinary and Animal SciencesUniversity of Massachusetts AmherstAmherstUSA

Personalised recommendations