Skewed Dendritic Cell Differentiation of MyD88-Deficient Donor Bone Marrow Cells, Instead of Massive Expansion as Myeloid-Derived Suppressor Cells, Aggravates GVHD
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Graft-versus-host disease (GVHD), a life-threatening complication after bone marrow transplantation (BMT), is induced by activation of alloreactive donor T cells. Our previous study demonstrated that transplantation of myeloid differentiation factor 88 (MyD88)-deficient knockout (KO) bone marrow (BM) resulted in aggravation of GVHD. Here, to understand the cellular mechanism, we performed longitudinal in vivo imaging and flow cytometric analyses followed by transcriptome and functional examination of donor MyD88-KO BM progenies in GVHD hosts, using a major histocompatibility complex-matched but minor histocompatibility antigen-mismatched C57BL/6→BALB.B model. In GVHD hosts with MyD88-KO BMT, donor BM-derived CD11b+Gr-1+ cells were found to undergo cell death, a fate significantly different from the explosive expansion shown by the wild type (WT) counterparts, and also from the moderate expansion of the WT or MyD88-KO BM-derived cells in non-GVHD hosts. It was also revealed that MyD88-KO CD11b+Gr-1+ cells preferred differentiation into CD11c+ dendritic cells (DCs) to expansion as myeloid-derived suppressor cells in GVHD hosts or in high inflammatory in vitro conditions. These CD11c+ DCs comprised the majority of MyD88-KO CD11b+Gr-1+ apoptotic cells in GVHD hosts. Their ability to cross-present alloantigens of host origin contributed to the enhancement of T cell alloreactivity, causing GVHD aggravation and eventually death through the killing function of activated T cells. These results provide insights into the roles of MyD88 in myelopoiesis of donor BM and the protective effects in GVHD hosts, helpful information for development of a strategy to control GVHD.
Abstract
Graft-versus-host disease (GVHD), a life-threatening complication after bone marrow transplantation (BMT), is induced by activation of alloreactive donor T cells. Our previous study demonstrated that transplantation of myeloid differentiation factor 88 (MyD88)-deficient knockout (KO) bone marrow (BM) resulted in aggravation of GVHD. Here, to understand the cellular mechanism, we performed longitudinal in vivo imaging and flow cytometric analyses followed by transcriptome and functional examination of donor MyD88-KO BM progenies in GVHD hosts, using a major histocompatibility complex-matched but minor histocompatibility antigen-mismatched C57BL/6→BALB.B model. In GVHD hosts with MyD88-KO BMT, donor BM-derived CD11b+Gr-1+ cells were found to undergo cell death, a fate significantly different from the explosive expansion shown by the wild type (WT) counterparts, and also from the moderate expansion of the WT or MyD88-KO BM-derived cells in non-GVHD hosts. It was also revealed that MyD88-KO CD11b+Gr-1+ cells preferred differentiation into CD11c+ dendritic cells (DCs) to expansion as myeloid-derived suppressor cells in GVHD hosts or in high inflammatory in vitro conditions. These CD11c+ DCs comprised the majority of MyD88-KO CD11b+Gr-1+ apoptotic cells in GVHD hosts. Their ability to cross-present alloantigens of host origin contributed to the enhancement of T cell alloreactivity, causing GVHD aggravation and eventually death through the killing function of activated T cells. These results provide insights into the roles of MyD88 in myelopoiesis of donor BM and the protective effects in GVHD hosts, helpful information for development of a strategy to control GVHD.
참고문헌 (52)
- Bolaños-Meade J, "Blood and marrow transplantation for sickle cell disease: overcoming barriers to success", Curr Opin Oncol, 21, pp.158~161 (2009)
- Jenq RR, "Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer", Nat Rev Cancer, 10, pp.213~221 (2010)
- Blazar BR, "Advances in graft-versus-host disease biology and therapy", Nat Rev Immunol, 12, pp.443~458 (2012)
- Shlomchik WD., "Graft-versus-host disease", Nat Rev Immunol, 7, pp.340~352 (2007)
- Wang D, "Dynamic change and impact of myeloid-derived suppressor cells in allogeneic bone marrow transplantation in mice", Biol Blood Marrow Transplant, 19, pp.692~702 (2013)
- 이영관, "TLR", MyD88-mediated Innate Immunity in Intestinal Graft-versus-Host Disease, 2017, pp.17(3), 144~151[DOI]
- Schölch S, "Radiotherapy combined with TLR7", 8 activation induces strong immune responses against gastrointestinal tumors, 2015, pp.6, 4663~4676
- Akira S, "Toll-like receptor signalling", Nat Rev Immunol, 4, pp.499~511 (2004)
- Yamamoto M, "Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway", Science, 301, pp.640~643 (2003)
- van der Zouwen B, "Alloreactive effector T cells require the local formation of a proinflammatory environment to allow crosstalk and high avidity interaction with nonhematopoietic tissues to induce GVHD reactivity", Biol Blood Marrow Transplant, 18, pp.1353~1367 (2012)
- Kinnier CV, "Innate immune activation by the viral PAMP poly I:C potentiates pulmonary graft-versus-host disease after allogeneic hematopoietic cell transplant", Transpl Immunol, 24, pp.83~93 (2011)
- Sinha P, "Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response", J Immunol, 179, pp.977~983 (2007)
- Gabrilovich DI, "Myeloid-derived suppressor cells as regulators of the immune system", Nat Rev Immunol, 9, pp.162~174 (2009)
- Gabrilovich DI, "Coordinated regulation of myeloid cells by tumours", Nat Rev Immunol, 12, pp.253~268 (2012)
- Veglia F, "Myeloid-derived suppressor cells coming of age", Nat Immunol, 19, pp.108~119 (2018)
- Youn JI, "Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice", J Leukoc Biol, 91, pp.167~181 (2012)
- Youn JI, "Subsets of myeloid-derived suppressor cells in tumor-bearing mice", J Immunol, 181, pp.5791~5802 (2008)
- Youn JI, "The biology of myeloid-derived suppressor cells: the blessing and the curse of morphological and functional heterogeneity", Eur J Immunol, 40, pp.2969~2975 (2010)
- Kumar V, "The nature of myeloid-derived suppressor cells in the tumor microenvironment", Trends Immunol, 37, pp.208~220 (2016)
- Choi EY, "Real-time T-cell profiling identifies H60 as a major minor histocompatibility antigen in murine graft-versus-host disease", Blood, 100, pp.4259~4265 (2002)
- Gabrilovich DI., "Myeloid-derived suppressor cells", Cancer Immunol Res, 5, pp.3~8 (2017)
- Lim JY, "Myd88 in donor bone marrow cells is critical for protection from acute intestinal graft-vs.-host disease", Mucosal Immunol, 9, pp.730~743 (2016)
- Highfill SL, "Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13", Blood, 116, pp.5738~5747 (2010)
- Koehn BH, "Role of myeloid-derived suppressor cells in allogeneic hematopoietic cell transplantation", J Leukoc Biol, 102, pp.335~341 (2017)
- Kawai T, "Unresponsiveness of MyD88-deficient mice to endotoxin", Immunity, 11, pp.115~122 (1999)
- Myung Geun Song, "In Vivo Imaging of Differences in Early Donor Cell Proliferation in Graft-Versus-Host Disease Hosts with Different Pre-Conditioning Doses", Molecules and Cells, 33(1), pp.79~86 (2012), 한국분자세포생물학회
- Kim J, "Memory programming in CD8(+) T-cell differentiation is intrinsic and is not determined by CD4 help", Nat Commun, 6, pp.7994~ (2015)
- Cooke KR, "An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin", Blood, 88, pp.3230~3239 (1996)
- Choi JY, "Long-term consumption of sugar-sweetened beverage during the growth period promotes social aggression in adult mice with proinflammatory responses in the brain", Sci Rep, 7, pp.45693~ (2017)
- Lutz MB, "Culture of bone marrow cells in GM-CSF plus high doses of lipopolysaccharide generates exclusively immature dendritic cells which induce alloantigen-specific CD4 T cell anergy in vitro", Eur J Immunol, 30, pp.1048~1052 (2000)
- Pfaller MA, "Global surveillance of in vitro activity of micafungin against Candida: a comparison with caspofungin by CLSI-recommended methods", J Clin Microbiol, 44, pp.3533~3538 (2006)
- 주지민, "Selection of Thymocytes Expressing Transgenic TCR Specific for a Minor Histocompatibility Antigen, H60", Immune Network, 15(5), pp.222~231 (2015), 대한면역학회[DOI]
- 유강일, "Subdominant H60 antigen-specific CD8 T-cell response precedes dominant H4 antigen-specific response during the initial phase of allogenic skin graft rejection", Experimental and Molecular Medicine, 47, pp.1~12 (2015), 생화학분자생물학회
- 주지민, "Kinetics of IFN-γ and IL-17 Production by CD4 and CD8 T Cells during Acute Graft-versus-Host Disease", Immune Network, 14(2), pp.89~99 (2014), 대한면역학회
- Hirayama M, "Tolerogenic effect of non-inherited maternal antigens in hematopoietic stem cell transplantation", Front Immunol, 3, pp.135~ (2012)
- Schinnerling K, "Gene expression profiling of human monocyte-derived dendritic cells - searching for molecular regulators of tolerogenicity", Front Immunol, 6, pp.528~ (2015)
- 전지영, "Characterization of CTL Clones Specific for Single Antigen, H60 Minor Histocompatibility Antigen", Immune Network, 11(2), pp.100~106 (2011), 대한면역학회
- Greifenberg V, "Myeloid-derived suppressor cell activation by combined LPS and IFN-gamma treatment impairs DC development", Eur J Immunol, 39, pp.2865~2876 (2009)
- Wang X, "Mechanisms of antigen presentation to T cells in murine graft-versus-host disease: cross-presentation and the appearance of cross-presentation", Blood, 118, pp.6426~6437 (2011)
- Kawai T, "The role of pattern-recognition receptors in innate immunity: update on toll-like receptors", Nat Immunol, 11, pp.373~384 (2010)
- O'Neill LA, "The family of five: TIR-domain-containing adaptors in toll-like receptor signalling", Nat Rev Immunol, 7, pp.353~364 (2007)
- Nagai Y, "Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment", Immunity, 24, pp.801~812 (2006)
- Takeda K, "Toll-like receptors", Annu Rev Immunol, 21, pp.335~376 (2003)
- Tu S, "Role of toll-like receptor signaling in the pathogenesis of graft-versus-host diseases", Int J Mol Sci, 17, pp.E1288~ (2016)
- Wang S, "Myd88 adaptor-dependent microbial sensing by regulatory t cells promotes mucosal tolerance and enforces commensalism", Immunity, 43, pp.289~303 (2015)
- Vander Lugt B, "Transcriptional programming of dendritic cells for enhanced MHC class II antigen presentation", Nat Immunol, 15, pp.161~167 (2014)
- Belz GT, "Transcriptional programming of the dendritic cell network", Nat Rev Immunol, 12, pp.101~113 (2012)
- Serbina NV, "TNF", iNOS-producing dendritic cells mediate innate immune defense against bacterial infection, 2003, pp.19, 59~70
- Tamura T, "IFN regulatory factor-4 and -8 govern dendritic cell subset development and their functional diversity", J Immunol, 174, pp.2573~2581 (2005)
- Tezuka H, "Regulation of IgA production by naturally occurring TNF", iNOS-producing dendritic cells, 2007, pp.448, 929~933
- Nam S, "Interferon regulatory factor 4 (IRF4) controls myeloid-derived suppressor cell (MDSC) differentiation and function", J Leukoc Biol, 100, pp.1273~1284 (2016)
- Valanparambil RM, "IRF-8 regulates expansion of myeloid-derived suppressor cells and Foxp3+ regulatory T cells and modulates Th2 immune responses to gastrointestinal nematode infection", PLoS Pathog, 13, pp.e1006647~ (2017)