Skewed dendritic cell differentiation of myd88-deficient donor bone marrow cells, instead of massive expansion as myeloid-derived suppressor cells, aggravates GVHD

Young Kwan Lee, Ji Min Ju, Woo Jeong Shon, Sehwa Oh, Chang Ki Min, Myung Soo Kang, Dong Mi Shin, Eun Young Choi

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish
Article numbere44
JournalImmune Network
Volume18
Issue number6
DOIs
StatePublished - Dec 2018

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Keywords

  • Bone marrow transplantation
  • Dendritic cells
  • Graft-versus-host disease
  • Myeloid differentiation factor 88
  • Myeloid-derived suppressor cells

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