Allogeneic transplantation of foreign organs or tissues has lifesaving potential, but can lead to serious complications. After solid organ transplantation, immune-mediated rejection mandates the use of prolonged global immunosuppression and limits the life span of transplanted allografts. After bone marrow transplantation, donor-derived immune cells can trigger life-threatening graft-versus-host disease. T cells are central mediators of alloimmune complications and the target of most existing therapeutic interventions. We review recent progress in identifying multiple cell types in addition to T cells and new molecular pathways that regulate pathogenic alloreactivity. Key discoveries include the cellular subsets that function as potential sources of alloantigens, the cross talk of innate lymphoid cells with damaged epithelia and with the recipient microbiome, the impact of the alarmin interleukin-33 on alloreactivity, and the role of Notch ligands expressed by fibroblastic stromal cells in alloimmunity. While refining our understanding of transplantation immunobiology, these findings identify new therapeutic targets and new areas of investigation.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Lindahl KF, Wilson DB. 1.  1977. Histocompatibility antigen-activated cytotoxic T lymphocytes. I. Estimates of the absolute frequency of killer cells generated in vitro. J. Exp. Med. 145:3500–7 [Google Scholar]
  2. Colf LA, Bankovich AJ, Hanick NA, Bowerman NA, Jones LL. 2.  et al. 2007. How a single T cell receptor recognizes both self and foreign MHC. Cell 129:1135–46 [Google Scholar]
  3. Macdonald WA, Chen Z, Gras S, Archbold JK, Tynan FE. 3.  et al. 2009. T cell allorecognition via molecular mimicry. Immunity 31:6897–908 [Google Scholar]
  4. Sprent J, Schaefer M, Lo D, Korngold R. 4.  1986. Properties of purified T cell subsets. II. In vivo responses to class I versus class II H-2 differences. J. Exp. Med. 163:4998–1011 [Google Scholar]
  5. Takemoto SK, Terasaki PI, Gjertson DW, Cecka JM. 5.  2000. Twelve years' experience with national sharing of HLA-matched cadaveric kidneys for transplantation. N. Engl. J. Med. 343:151078–84 [Google Scholar]
  6. Wang W, Meadows LR, den Haan JM, Sherman NE, Chen Y. 6.  et al. 1995. Human H-Y: a male-specific histocompatibility antigen derived from the SMCY protein. Science 269:52301588–90 [Google Scholar]
  7. Martin PJ, Levine DM, Storer BE, Warren EH, Zheng X. 7.  et al. 2017. Genome-wide minor histocompatibility matching as related to the risk of graft-versus-host disease. Blood 129:6791–98 [Google Scholar]
  8. Spierings E, Kim YH, Hendriks M, Borst E, Sergeant R. 8.  et al. 2013. Multicenter analyses demonstrate significant clinical effects of minor histocompatibility antigens on GvHD and GvL after HLA-matched related and unrelated hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 19:81244–53 [Google Scholar]
  9. Miconnet I, Roger T, Seman M, Bruley-Rosset M. 9.  1995. Critical role of endogenous Mtv in acute lethal graft-versus-host disease. Eur. J. Immunol. 25:2364–68 [Google Scholar]
  10. Shlomchik WD, Couzens MS, Tang CB, McNiff J, Robert ME. 10.  et al. 1999. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 285:5426412–15 [Google Scholar]
  11. Koyama M, Kuns RD, Olver SD, Raffelt NC, Wilson YA. 11.  et al. 2012. Recipient nonhematopoietic antigen-presenting cells are sufficient to induce lethal acute graft-versus-host disease. Nat. Med. 18:1135–42 [Google Scholar]
  12. Matte CC, Liu J, Cormier J, Anderson BE, Athanasiadis I. 12.  et al. 2004. Donor APCs are required for maximal GVHD but not for GVL. Nat. Med. 10:9987–92 [Google Scholar]
  13. Markey KA, Banovic T, Kuns RD, Olver SD, Don AL. 13.  et al. 2009. Conventional dendritic cells are the critical donor APC presenting alloantigen after experimental bone marrow transplantation. Blood 113:225644–49 [Google Scholar]
  14. Anderson BE, McNiff JM, Jain D, Blazar BR, Shlomchik WD, Shlomchik MJ. 14.  2005. Distinct roles for donor- and host-derived antigen-presenting cells and costimulatory molecules in murine chronic graft-versus-host disease: Requirements depend on target organ. Blood 105:52227–34 [Google Scholar]
  15. Koyama M, Cheong M, Markey KA, Gartlan KH, Kuns RD. 15.  et al. 2015. Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease. J. Exp. Med. 212:81303–21 [Google Scholar]
  16. Leveque-El Mouttie L, Koyama M, Le Texier L, Markey KA, Cheong M. 16.  et al. 2016. Corruption of dendritic cell antigen presentation during acute GVHD leads to regulatory T-cell failure and chronic GVHD. Blood 128:6794–804 [Google Scholar]
  17. Wikstrom ME, Fleming P, Kuns RD, Schuster IS, Voigt V. 17.  et al. 2015. Acute GVHD results in a severe DC defect that prevents T-cell priming and leads to fulminant cytomegalovirus disease in mice. Blood 126:121503–14 [Google Scholar]
  18. Teshima T, Ordemann R, Reddy P, Gagin S, Liu C. 18.  et al. 2002. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat. Med. 8:6575–81 [Google Scholar]
  19. Duffner UA, Maeda Y, Cooke KR, Reddy P, Ordemann R. 19.  et al. 2004. Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease. J. Immunol. 172:127393–98 [Google Scholar]
  20. Koyama M, Hashimoto D, Aoyama K, Matsuoka K, Karube K. 20.  et al. 2009. Plasmacytoid dendritic cells prime alloreactive T cells to mediate graft-versus-host disease as antigen-presenting cells. Blood 113:92088–95 [Google Scholar]
  21. Li H, Demetris AJ, McNiff J, Matte-Martone C, Tan HS. 21.  et al. 2012. Profound depletion of host conventional dendritic cells, plasmacytoid dendritic cells, and B cells does not prevent graft-versus-host disease induction. J. Immunol. 188:83804–11 [Google Scholar]
  22. Weber M, Rudolph B, Stein P, Yogev N, Bosmann M. 22.  et al. 2014. Host-derived CD8+ dendritic cells protect against acute graft-versus-host disease after experimental allogeneic bone marrow transplantation. Biol. Blood Marrow Transplant. 20:111696–704 [Google Scholar]
  23. Teshima T, Reddy P, Lowler KP, KuKuruga MA, Liu C. 23.  et al. 2002. Flt3 ligand therapy for recipients of allogeneic bone marrow transplants expands host CD8α+ dendritic cells and reduces experimental acute graft-versus-host disease. Blood 99:51825–32 [Google Scholar]
  24. Zhang Y, Louboutin JP, Zhu J, Rivera AJ, Emerson SG. 24.  2002. Preterminal host dendritic cells in irradiated mice prime CD8+ T cell–mediated acute graft-versus-host disease. J. Clin. Investig. 109:101335–44 [Google Scholar]
  25. Matte-Martone C, Liu J, Jain D, McNiff J, Shlomchik WD. 25.  2008. CD8+ but not CD4+ T cells require cognate interactions with target tissues to mediate GVHD across only minor H antigens, whereas both CD4+ and CD8+ T cells require direct leukemic contact to mediate GVL. Blood 111:73884–92 [Google Scholar]
  26. Jones SC, Murphy GF, Friedman TM, Korngold R. 26.  2003. Importance of minor histocompatibility antigen expression by nonhematopoietic tissues in a CD4+ T cell–mediated graft-versus-host disease model. J. Clin. Investig. 112:121880–86 [Google Scholar]
  27. Toubai T, Tawara I, Sun Y, Liu C, Nieves E. 27.  et al. 2012. Induction of acute GVHD by sex-mismatched H-Y antigens in the absence of functional radiosensitive host hematopoietic-derived antigen-presenting cells. Blood 119:163844–53 [Google Scholar]
  28. Tawara I, Shlomchik WD, Jones A, Zou W, Nieves E. 28.  et al. 2010. A crucial role for host APCs in the induction of donor CD4+CD25+ regulatory T cell–mediated suppression of experimental graft-versus-host disease. J. Immunol. 185:73866–72 [Google Scholar]
  29. Steimle V, Otten LA, Zufferey M, Mach B. 29.  1993. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell 75:1135–46 [Google Scholar]
  30. Steimle V, Siegrist CA, Mottet A, Lisowska-Grospierre B, Mach B. 30.  1994. Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA. . Science 265:5168106–9 [Google Scholar]
  31. Li H, Matte-Martone C, Tan HS, Venkatesan S, McNiff J. 31.  et al. 2011. Graft-versus-host disease is independent of innate signaling pathways triggered by pathogens in host hematopoietic cells. J. Immunol. 186:1230–41 [Google Scholar]
  32. Saada JI, Pinchuk IV, Barrera CA, Adegboyega PA, Suarez G. 32.  et al. 2006. Subepithelial myofibroblasts are novel nonprofessional APCs in the human colonic mucosa. J. Immunol. 177:95968–79 [Google Scholar]
  33. Pinchuk IV, Saada JI, Beswick EJ, Boya G, Qiu SM. 33.  et al. 2008. PD-1 ligand expression by human colonic myofibroblasts/fibroblasts regulates CD4+ T cell activity. Gastroenterology 135:41228–37 [Google Scholar]
  34. Mayer L, Shlien R. 34.  1987. Evidence for function of Ia molecules on gut epithelial cells in man. J. Exp. Med. 166:51471–83 [Google Scholar]
  35. Hershberg RM, Cho DH, Youakim A, Bradley MB, Lee JS. 35.  et al. 1998. Highly polarized HLA class II antigen processing and presentation by human intestinal epithelial cells. J. Clin. Investig. 102:4792–803 [Google Scholar]
  36. Westendorf AM, Fleissner D, Groebe L, Jung S, Gruber AD. 36.  et al. 2009. CD4+Foxp3+ regulatory T cell expansion induced by antigen-driven interaction with intestinal epithelial cells independent of local dendritic cells. Gut 58:2211–19 [Google Scholar]
  37. Silva IA, Olkiewicz K, Askew D, Fisher JM, Chaudhary MN. 37.  et al. 2010. Secondary lymphoid organs contribute to, but are not required for the induction of graft-versus-host responses following allogeneic bone marrow transplantation: a shifting paradigm for T cell allo-activation. Biol. Blood Marrow Transplant. 16:5598–611 [Google Scholar]
  38. Malhotra D, Fletcher AL, Astarita J, Lukacs-Kornek V, Tayalia P. 38.  et al. 2012. Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks. Nat. Immunol. 13:5499–510 [Google Scholar]
  39. Fletcher AL, Lukacs-Kornek V, Reynoso ED, Pinner SE, Bellemare-Pelletier A. 39.  et al. 2010. Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J. Exp. Med. 207:4689–97 [Google Scholar]
  40. Abe J, Shichino S, Ueha S, Hashimoto S, Tomura M. 40.  et al. 2014. Lymph node stromal cells negatively regulate antigen-specific CD4+ T cell responses. J. Immunol. 193:41636–44 [Google Scholar]
  41. Chung J, Ebens CL, Perkey E, Radojcic V, Koch U. 41.  et al. 2017. Fibroblastic niches prime T cell alloimmunity through Delta-like Notch ligands. J. Clin. Investig. 127:41574–88 [Google Scholar]
  42. Dubrot J, Duraes FV, Potin L, Capotosti F, Brighouse D. 42.  et al. 2014. Lymph node stromal cells acquire peptide-MHCII complexes from dendritic cells and induce antigen-specific CD4+ T cell tolerance. J. Exp. Med. 211:61153–66 [Google Scholar]
  43. Kundig TM, Bachmann MF, DiPaolo C, Simard JJ, Battegay M. 43.  et al. 1995. Fibroblasts as efficient antigen-presenting cells in lymphoid organs. Science 268:52151343–47 [Google Scholar]
  44. Suenaga F, Ueha S, Abe J, Kosugi-Kanaya M, Wang Y. 44.  et al. 2015. Loss of lymph node fibroblastic reticular cells and high endothelial cells is associated with humoral immunodeficiency in mouse graft-versus-host disease. J. Immunol. 194:1398–406 [Google Scholar]
  45. Lechler RI, Batchelor JR. 45.  1982. Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of donor strain dendritic cells. J. Exp. Med. 155:131–41 [Google Scholar]
  46. Benichou G, Takizawa PA, Olson CA, McMillan M, Sercarz EE. 46.  1992. Donor major histocompatibility complex (MHC) peptides are presented by recipient MHC molecules during graft rejection. J. Exp. Med. 175:1305–8 [Google Scholar]
  47. Benichou G, Fedoseyeva E, Lehmann PV, Olson CA, Geysen HM. 47.  et al. 1994. Limited T cell response to donor MHC peptides during allograft rejection. Implications for selective immune therapy in transplantation. J. Immunol. 153:3938–45 [Google Scholar]
  48. Illigens BM, Yamada A, Fedoseyeva EV, Anosova N, Boisgerault F. 48.  et al. 2002. The relative contribution of direct and indirect antigen recognition pathways to the alloresponse and graft rejection depends upon the nature of the transplant. Hum. Immunol. 63:10912–25 [Google Scholar]
  49. Baker RJ, Hernandez-Fuentes MP, Brookes PA, Chaudhry AN, Cook HT, Lechler RI. 49.  2001. Loss of direct and maintenance of indirect alloresponses in renal allograft recipients: implications for the pathogenesis of chronic allograft nephropathy. J. Immunol. 167:127199–206 [Google Scholar]
  50. Liu Q, Rojas-Canales DM, Divito SJ, Shufesky WJ, Stolz DB. 50.  et al. 2016. Donor dendritic cell-derived exosomes promote allograft-targeting immune response. J. Clin. Investig. 126:82805–20 [Google Scholar]
  51. Marino J, Babiker-Mohamed MH, Crosby-Bertorini P, Paster JT, LeGuern C. 51.  et al. 2016. Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation. Sci. Immunol. 1:1aaf8759 [Google Scholar]
  52. Herrera OB, Golshayan D, Tibbott R, Salcido Ochoa F, James MJ. 52.  et al. 2004. A novel pathway of alloantigen presentation by dendritic cells. J. Immunol. 173:84828–37 [Google Scholar]
  53. Markey KA, Koyama M, Gartlan KH, Leveque L, Kuns RD. 53.  et al. 2014. Cross-dressing by donor dendritic cells after allogeneic bone marrow transplantation contributes to formation of the immunological synapse and maximizes responses to indirectly presented antigen. J. Immunol. 192:115426–33 [Google Scholar]
  54. Sivaganesh S, Harper SJ, Conlon TM, Callaghan CJ, Saeb-Parsy K. 54.  et al. 2013. Copresentation of intact and processed MHC alloantigen by recipient dendritic cells enables delivery of linked help to alloreactive CD8 T cells by indirect-pathway CD4 T cells. J. Immunol. 190:115829–38 [Google Scholar]
  55. Zhuang Q, Liu Q, Divito SJ, Zeng Q, Yatim KM. 55.  et al. 2016. Graft-infiltrating host dendritic cells play a key role in organ transplant rejection. Nat. Commun. 7:12623 [Google Scholar]
  56. Ochando JC, Homma C, Yang Y, Hidalgo A, Garin A. 56.  et al. 2006. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat. Immunol. 7:6652–62 [Google Scholar]
  57. Heeger PS, Greenspan NS, Kuhlenschmidt S, Dejelo C, Hricik DE. 57.  et al. 1999. Pretransplant frequency of donor-specific, IFN-γ-producing lymphocytes is a manifestation of immunologic memory and correlates with the risk of posttransplant rejection episodes. J. Immunol. 163:42267–75 [Google Scholar]
  58. Abrahimi P, Qin L, Chang WG, Bothwell AL, Tellides G. 58.  et al. 2016. Blocking MHC class II on human endothelium mitigates acute rejection. JCI Insight 1:1e85293 [Google Scholar]
  59. Hill GR, Crawford JM, Cooke KR, Brinson YS, Pan L, Ferrara JL. 59.  1997. Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood 90:83204–13 [Google Scholar]
  60. Beilhack A, Schulz S, Baker J, Beilhack GF, Wieland CB. 60.  et al. 2005. In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets. Blood 106:31113–22 [Google Scholar]
  61. Artis D, Spits H. 61.  2015. The biology of innate lymphoid cells. Nature 517:7534293–301 [Google Scholar]
  62. Hanash AM, Dudakov JA, Hua G, O'Connor MH, Young LF. 62.  et al. 2012. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity 37:2339–50 [Google Scholar]
  63. Dudakov JA, Hanash AM, Jenq RR, Young LF, Ghosh A. 63.  et al. 2012. Interleukin-22 drives endogenous thymic regeneration in mice. Science 336:607791–95 [Google Scholar]
  64. Clift RA, Buckner CD, Appelbaum FR, Bearman SI, Petersen FB. 64.  et al. 1990. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood 76:91867–71 [Google Scholar]
  65. Eriguchi Y, Takashima S, Oka H, Shimoji S, Nakamura K. 65.  et al. 2012. Graft-versus-host disease disrupts intestinal microbial ecology by inhibiting Paneth cell production of α-defensins. Blood 120:1223–31 [Google Scholar]
  66. Jenq RR, Ubeda C, Taur Y, Menezes CC, Khanin R. 66.  et al. 2012. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J. Exp. Med. 209:5903–11 [Google Scholar]
  67. Jenq RR, Taur Y, Devlin SM, Ponce DM, Goldberg JD. 67.  et al. 2015. Intestinal blautia is associated with reduced death from graft-versus-host disease. Biol. Blood Marrow Transplant. 21:81373–83 [Google Scholar]
  68. Shono Y, Docampo MD, Peled JU, Perobelli SM, Velardi E. 68.  et al. 2016. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice. Sci. Transl. Med. 8:339339ra71 [Google Scholar]
  69. Takashima S, Kadowaki M, Aoyama K, Koyama M, Oshima T. 69.  et al. 2011. The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells. J. Exp. Med. 208:2285–94 [Google Scholar]
  70. Lindemans CA, Calafiore M, Mertelsmann AM, O'Connor MH, Dudakov JA. 70.  et al. 2015. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528:7583560–64 [Google Scholar]
  71. Levine JE, Huber E, Hammer ST, Harris AC, Greenson JK. 71.  et al. 2013. Low Paneth cell numbers at onset of gastrointestinal graft-versus-host disease identify patients at high risk for nonrelapse mortality. Blood 122:81505–9 [Google Scholar]
  72. Sato T, van Es JH, Snippert HJ, Stange DE, Vries RG. 72.  et al. 2011. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469:7330415–18 [Google Scholar]
  73. Vaishnava S, Yamamoto M, Severson KM, Ruhn KA, Yu X. 73.  et al. 2011. The antibacterial lectin RegIIIγ promotes the spatial segregation of microbiota and host in the intestine. Science 334:6053255–58 [Google Scholar]
  74. Ferrara JL, Harris AC, Greenson JK, Braun TM, Holler E. 74.  et al. 2011. Regenerating islet-derived 3α is a biomarker of gastrointestinal graft-versus-host disease. Blood 118:256702–8 [Google Scholar]
  75. Dudakov JA, Hanash AM, van den Brink MR. 75.  2015. Interleukin-22: immunobiology and pathology. Annu. Rev. Immunol. 33:747–85 [Google Scholar]
  76. Hepworth MR, Fung TC, Masur SH, Kelsen JR, McConnell FM. 76.  et al. 2015. Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells. Science 348:62381031–35 [Google Scholar]
  77. Couturier M, Lamarthee B, Arbez J, Renauld JC, Bossard C. 77.  et al. 2013. IL-22 deficiency in donor T cells attenuates murine acute graft-versus-host disease mortality while sparing the graft-versus-leukemia effect. Leukemia 27:71527–37 [Google Scholar]
  78. Zhao K, Zhao D, Huang D, Yin L, Chen C. 78.  et al. 2014. Interleukin-22 aggravates murine acute graft-versus-host disease by expanding effector T cell and reducing regulatory T cell. J. Interferon Cytokine Res. 34:9707–15 [Google Scholar]
  79. Weiner J, Zuber J, Shonts B, Yang S, Fu J. 79.  et al. 2017. Long-term persistence of innate lymphoid cells in the gut after intestinal transplantation. Transplantation 101:102449–54 [Google Scholar]
  80. Talayero P, Mancebo E, Calvo-Pulido J, Rodriguez-Munoz S, Bernardo I. 80.  et al. 2016. Innate lymphoid cells groups 1 and 3 in the epithelial compartment of functional human intestinal allografts. Am. J. Transplant. 16:172–82 [Google Scholar]
  81. Bjorklund AK, Forkel M, Picelli S, Konya V, Theorell J. 81.  et al. 2016. The heterogeneity of human CD127+ innate lymphoid cells revealed by single-cell RNA sequencing. Nat. Immunol. 17:4451–60 [Google Scholar]
  82. 82. Human Microbiome Project Consort. 2012. A framework for human microbiome research. Nature 486:7402215–21 [Google Scholar]
  83. van Bekkum DW, Roodenburg J, Heidt PJ, van der Waaij D. 83.  1974. Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora. J. Natl. Cancer Inst. 52:2401–4 [Google Scholar]
  84. Storb R, Prentice RL, Buckner CD, Clift RA, Appelbaum F. 84.  et al. 1983. Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings. Beneficial effect of a protective environment. N. Engl. J. Med. 308:6302–7 [Google Scholar]
  85. Beelen DW, Elmaagacli A, Muller KD, Hirche H, Schaefer UW. 85.  1999. Influence of intestinal bacterial decontamination using metronidazole and ciprofloxacin or ciprofloxacin alone on the development of acute graft-versus-host disease after marrow transplantation in patients with hematologic malignancies: final results and long-term follow-up of an open-label prospective randomized trial. Blood 93:103267–75 [Google Scholar]
  86. Weber D, Jenq RR, Peled JU, Taur Y, Hiergeist A. 86.  et al. 2017. Microbiota disruption induced by early use of broad-spectrum antibiotics is an independent risk factor of outcome after allogeneic stem cell transplantation. Biol. Blood Marrow Transplant. 23:5845–52 [Google Scholar]
  87. Varelias A, Ormerod KL, Bunting MD, Koyama M, Gartlan KH. 87.  et al. 2017. Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome. Blood 129:152172–85 [Google Scholar]
  88. Weber D, Oefner PJ, Dettmer K, Hiergeist A, Koestler J. 88.  et al. 2016. Rifaximin preserves intestinal microbiota balance in patients undergoing allogeneic stem cell transplantation. Bone Marrow Transplant 51:81087–92 [Google Scholar]
  89. Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N. 89.  et al. 2013. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342:6161967–70 [Google Scholar]
  90. Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillere R. 90.  et al. 2013. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342:6161971–76 [Google Scholar]
  91. Oh PL, Martinez I, Sun Y, Walter J, Peterson DA, Mercer DF. 91.  2012. Characterization of the ileal microbiota in rejecting and nonrejecting recipients of small bowel transplants. Am. J. Transplant. 12:3753–62 [Google Scholar]
  92. Botha P, Archer L, Anderson RL, Lordan J, Dark JH. 92.  et al. 2008. Pseudomonas aeruginosa colonization of the allograft after lung transplantation and the risk of bronchiolitis obliterans syndrome. Transplantation 85:5771–74 [Google Scholar]
  93. Willner DL, Hugenholtz P, Yerkovich ST, Tan ME, Daly JN. 93.  et al. 2013. Reestablishment of recipient-associated microbiota in the lung allograft is linked to reduced risk of bronchiolitis obliterans syndrome. Am. J. Respir. Crit. Care Med. 187:6640–47 [Google Scholar]
  94. Dickson RP, Erb-Downward JR, Freeman CM, Walker N, Scales BS. 94.  et al. 2014. Changes in the lung microbiome following lung transplantation include the emergence of two distinct Pseudomonas species with distinct clinical associations. PLOS ONE 9:5e97214 [Google Scholar]
  95. Fricke WF, Maddox C, Song Y, Bromberg JS. 95.  2014. Human microbiota characterization in the course of renal transplantation. Am. J. Transplant. 14:2416–27 [Google Scholar]
  96. Wang T, Ahmed EB, Chen L, Xu J, Tao J. 96.  et al. 2010. Infection with the intracellular bacterium, Listeriamonocytogenes, overrides established tolerance in a mouse cardiac allograft model. Am. J. Transplant. 10:71524–33 [Google Scholar]
  97. Ahmed EB, Wang T, Daniels M, Alegre ML, Chong AS. 97.  2011. IL-6 induced by Staphylococcus aureus infection prevents the induction of skin allograft acceptance in mice. Am. J. Transplant. 11:5936–46 [Google Scholar]
  98. Lei YM, Chen L, Wang Y, Stefka AT, Molinero LL. 98.  et al. 2016. The composition of the microbiota modulates allograft rejection. J. Clin. Investig. 126:72736–44 [Google Scholar]
  99. Corbitt N, Kimura S, Isse K, Specht S, Chedwick L. 99.  et al. 2013. Gut bacteria drive Kupffer cell expansion via MAMP-mediated ICAM-1 induction on sinusoidal endothelium and influence preservation-reperfusion injury after orthotopic liver transplantation. Am. J. Pathol. 182:1180–91 [Google Scholar]
  100. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA. 100.  et al. 2013. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:6145569–73 [Google Scholar]
  101. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G. 101.  et al. 2013. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504:7480446–50 [Google Scholar]
  102. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J. 102.  et al. 2013. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504:7480451–55 [Google Scholar]
  103. Mathewson ND, Jenq R, Mathew AV, Koenigsknecht M, Hanash A. 103.  et al. 2016. Gut microbiome-derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat. Immunol. 17:5505–13 [Google Scholar]
  104. Schmitz J, Owyang A, Oldham E, Song Y, Murphy E. 104.  et al. 2005. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23:5479–90 [Google Scholar]
  105. Molofsky AB, Savage AK, Locksley RM. 105.  2015. Interleukin-33 in tissue homeostasis, injury, and inflammation. Immunity 42:61005–19 [Google Scholar]
  106. Liew FY, Girard JP, Turnquist HR. 106.  2016. Interleukin-33 in health and disease. Nat. Rev. Immunol. 16:11676–89 [Google Scholar]
  107. Yin H, Li XY, Jin XB, Zhang BB, Gong Q. 107.  et al. 2010. IL-33 prolongs murine cardiac allograft survival through induction of TH2-type immune deviation. Transplantation 89:101189–97 [Google Scholar]
  108. Brunner SM, Schiechl G, Falk W, Schlitt HJ, Geissler EK, Fichtner-Feigl S. 108.  2011. Interleukin-33 prolongs allograft survival during chronic cardiac rejection. Transpl. Int. 24:101027–39 [Google Scholar]
  109. Turnquist HR, Zhao Z, Rosborough BR, Liu Q, Castellaneta A. 109.  et al. 2011. IL-33 expands suppressive CD11b+ Gr-1int and regulatory T cells, including ST2L+ Foxp3+ cells, and mediates regulatory T cell-dependent promotion of cardiac allograft survival. J. Immunol. 187:94598–610 [Google Scholar]
  110. Matta BM, Lott JM, Mathews LR, Liu Q, Rosborough BR. 110.  et al. 2014. IL-33 is an unconventional alarmin that stimulates IL-2 secretion by dendritic cells to selectively expand IL-33R/ST2+ regulatory T cells. J. Immunol. 193:84010–20 [Google Scholar]
  111. Pascual-Figal DA, Garrido IP, Blanco R, Minguela A, Lax A. 111.  et al. 2011. Soluble ST2 is a marker for acute cardiac allograft rejection. Ann. Thorac. Surg. 92:62118–24 [Google Scholar]
  112. Mathews LR, Lott JM, Isse K, Lesniak A, Landsittel D. 112.  et al. 2016. Elevated ST2 distinguishes incidences of pediatric heart and small bowel transplant rejection. Am. J. Transplant. 16:3938–50 [Google Scholar]
  113. Vander Lugt MT, Braun TM, Hanash S, Ritz J, Ho VT. 113.  et al. 2013. ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death. N. Engl. J. Med. 369:6529–39 [Google Scholar]
  114. Reichenbach DK, Schwarze V, Matta BM, Tkachev V, Lieberknecht E. 114.  et al. 2015. The IL-33/ST2 axis augments effector T-cell responses during acute GVHD. Blood 125:203183–92 [Google Scholar]
  115. Zhang J, Ramadan AM, Griesenauer B, Li W, Turner MJ. 115.  et al. 2015. ST2 blockade reduces sST2-producing T cells while maintaining protective mST2-expressing T cells during graft-versus-host disease. Sci. Transl. Med. 7:308308ra160 [Google Scholar]
  116. Matta BM, Reichenbach DK, Zhang X, Mathews L, Koehn BH. 116.  et al. 2016. Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD. Blood 128:3427–39 [Google Scholar]
  117. Zhang Y, Sandy AR, Wang J, Radojcic V, Shan GT. 117.  et al. 2011. Notch signaling is a critical regulator of allogeneic CD4+ T-cell responses mediating graft-versus-host disease. Blood 117:1299–308 [Google Scholar]
  118. Riella LV, Ueno T, Batal I, De Serres SA, Bassil R. 118.  et al. 2011. Blockade of Notch ligand Delta1 promotes allograft survival by inhibiting alloreactive Th1 cells and cytotoxic T cell generation. J. Immunol. 187:94629–38 [Google Scholar]
  119. Tran IT, Sandy AR, Carulli AJ, Ebens C, Chung J. 119.  et al. 2013. Blockade of individual Notch ligands and receptors controls graft-versus-host disease. J. Clin. Investig. 123:41590–604 [Google Scholar]
  120. Wood S, Feng J, Chung J, Radojcic V, Sandy-Sloat AR. 120.  et al. 2015. Transient blockade of Delta-like Notch ligands prevents allograft rejection mediated by cellular and humoral mechanisms in a mouse model of heart transplantation. J. Immunol. 194:62899–908 [Google Scholar]
  121. Sandy A, Chung J, Toubai T, Shan G, Tran I. 121.  et al. 2013. T cell–specific Notch inhibition blocks graft-versus-host disease by inducing a hyporesponsive program in alloreactive CD4+ and CD8+ T cells. J. Immunol. 190:115818–28 [Google Scholar]
  122. Charbonnier LM, Wang S, Georgiev P, Sefik E, Chatila TA. 122.  2015. Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling. Nat. Immunol. 16:1162–73 [Google Scholar]
  123. Mochizuki K, Xie F, He S, Tong Q, Liu Y. 123.  et al. 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. J. Immunol. 190:73772–82 [Google Scholar]
  124. Kovall RA, Gebelein B, Sprinzak D, Kopan R. 124.  2017. The canonical Notch signaling pathway: structural and biochemical insights into shape, sugar and force. Dev. Cell 41:3228–41 [Google Scholar]
  125. Auderset F, Schuster S, Coutaz M, Koch U, Desgranges F. 125.  et al. 2012. Redundant Notch1 and Notch2 signaling is necessary for IFNγ secretion by T helper 1 cells during infection with Leishmania major. . PLOS Pathog 8:3e1002560 [Google Scholar]
  126. Shin HM, Minter LM, Cho OH, Gottipati S, Fauq AH. 126.  et al. 2006. Notch1 augments NF-κB activity by facilitating its nuclear retention. EMBO J 25:1129–38 [Google Scholar]
  127. Wang H, Zang C, Taing L, Arnett KL, Wong YJ. 127.  et al. 2014. NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers. PNAS 111:2705–10 [Google Scholar]
  128. Herranz D, Ambesi-Impiombato A, Palomero T, Schnell SA, Belver L. 128.  et al. 2014. A NOTCH1-driven MYC enhancer promotes T cell development, transformation and acute lymphoblastic leukemia. Nat. Med. 20:101130–37 [Google Scholar]
  129. Radtke F, Wilson A, Stark G, Bauer M, van Meerwijk J. 129.  et al. 1999. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10:5547–58 [Google Scholar]
  130. Hozumi K, Mailhos C, Negishi N, Hirano K, Yahata T. 130.  et al. 2008. Delta-like 4 is indispensable in thymic environment specific for T cell development. J. Exp. Med. 205:112507–13 [Google Scholar]
  131. Koch U, Fiorini E, Benedito R, Besseyrias V, Schuster-Gossler K. 131.  et al. 2008. Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment. J. Exp. Med. 205:112515–23 [Google Scholar]
  132. Radtke F, MacDonald HR, Tacchini-Cottier F. 132.  2013. Regulation of innate and adaptive immunity by Notch. Nat. Rev. Immunol. 13:6427–37 [Google Scholar]
  133. Fasnacht N, Huang HY, Koch U, Favre S, Auderset F. 133.  et al. 2014. Specific fibroblastic niches in secondary lymphoid organs orchestrate distinct Notch-regulated immune responses. J. Exp. Med. 211:112265–79 [Google Scholar]
  134. Backer RA, Helbig C, Gentek R, Kent A, Laidlaw BJ. 134.  et al. 2014. A central role for Notch in effector CD8+ T cell differentiation. Nat. Immunol. 15:121143–51 [Google Scholar]
  135. Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, Flavell RA. 135.  2004. Instruction of distinct CD4 T helper cell fates by different Notch ligands on antigen-presenting cells. Cell 117:4515–26 [Google Scholar]
  136. Laky K, Evans S, Perez-Diez A, Fowlkes BJ. 136.  2015. Notch signaling regulates antigen sensitivity of naive CD4+ T cells by tuning co-stimulation. Immunity 42:180–94 [Google Scholar]
  137. Bailis W, Yashiro-Ohtani Y, Fang TC, Hatton RD, Weaver CT. 137.  et al. 2013. Notch simultaneously orchestrates multiple helper T cell programs independently of cytokine signals. Immunity 39:1148–59 [Google Scholar]
  138. Minter LM, Turley DM, Das P, Shin HM, Joshi I. 138.  et al. 2005. Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. . Nat. Immunol. 6:7680–88 [Google Scholar]
  139. Roderick JE, Gonzalez-Perez G, Kuksin CA, Dongre A, Roberts ER. 139.  et al. 2013. Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia. J. Exp. Med. 210:71311–29 [Google Scholar]
  140. Wong KK, Carpenter MJ, Young LL, Walker SJ, McKenzie G. 140.  et al. 2003. Notch ligation by Delta1 inhibits peripheral immune responses to transplantation antigens by a CD8+ cell-dependent mechanism. J. Clin. Investig. 112:111741–50 [Google Scholar]
  141. Hoyne GF, Le Roux I, Corsin-Jimenez M, Tan K, Dunne J. 141.  et al. 2000. Serrate1-induced Notch signalling regulates the decision between immunity and tolerance made by peripheral CD4+ T cells. Int. Immunol. 12:2177–85 [Google Scholar]
  142. Yvon ES, Vigouroux S, Rousseau RF, Biagi E, Amrolia P. 142.  et al. 2003. Overexpression of the Notch ligand, Jagged-1, induces alloantigen-specific human regulatory T cells. Blood 102:103815–21 [Google Scholar]
  143. Vigouroux S, Yvon E, Wagner HJ, Biagi E, Dotti G. 143.  et al. 2003. Induction of antigen-specific regulatory T cells following overexpression of a Notch ligand by human B lymphocytes. J. Virol. 77:2010872–80 [Google Scholar]
  144. Poe JC, Jia W, Su H, Anand S, Rose JJ. 144.  et al. 2017. An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD. Blood 130:192131–45 [Google Scholar]
  145. Reynolds ND, Lukacs NW, Long N, Karpus WJ. 145.  2011. Delta-like ligand 4 regulates central nervous system T cell accumulation during experimental autoimmune encephalomyelitis. J. Immunol. 187:52803–13 [Google Scholar]
  146. Chai Q, Onder L, Scandella E, Gil-Cruz C, Perez-Shibayama C. 146.  et al. 2013. Maturation of lymph node fibroblastic reticular cells from myofibroblastic precursors is critical for antiviral immunity. Immunity 38:51013–24 [Google Scholar]
  147. Calderon L, Boehm T. 147.  2012. Synergistic, context-dependent, and hierarchical functions of epithelial components in thymic microenvironments. Cell 149:1159–72 [Google Scholar]
  148. Reshef R, Luger SM, Hexner EO, Loren AW, Frey NV. 148.  et al. 2012. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N. Engl. J. Med. 367:2135–45 [Google Scholar]
  149. Sarantopoulos S, Ritz J. 149.  2015. Aberrant B-cell homeostasis in chronic GVHD. Blood 125:111703–7 [Google Scholar]
  150. Karahan GE, Class FH, Heidt S. 150.  2016. B cell immunity in solid organ transplantation. Front. Immunol. 7:686 [Google Scholar]
  151. Stolp J, Turka LA, Wood KJ. 151.  2014. B cells with immune-regulating function in transplantation. Nat. Rev. Nephrol. 10:7389–97 [Google Scholar]
  152. Chong AS, Sciammas R. 152.  Memory B cells in transplantation. Transplantation 99:121–8 [Google Scholar]
  153. Highfill SL, Rodriguez PC, Zhou Q, Goetz CA, Koehn BH. 153.  et al. 2010. Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is upregulated by interleukin-13. Blood 116:5738–47 [Google Scholar]
  154. Alexander KA, Flynn R, Lineburg KE, Kuns RD, Teal BE. 154.  et al. 2014. CSF-1-dependant donor-derived macrophages mediate chronic graft-versus-host disease. J. Clin. Investig. 124:104266–80 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error