Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Differential Effect of MyD88 Signal in Donor T Cells on Graft-versus-Leukemia Effect and Graft-versus-Host Disease after Experimental Allogeneic Stem Cell Transplantation

  • Lim, Ji-Young (Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea) ;
  • Ryu, Da-Bin (Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea) ;
  • Lee, Sung-Eun (Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea) ;
  • Park, Gyeongsin (Department of Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea) ;
  • Choi, Eun Young (Department of Biomedical Sciences, Seoul National University College of Medicine) ;
  • Min, Chang-Ki (Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea)
  • Received : 2015.06.02
  • Accepted : 2015.07.30
  • Published : 2015.11.30
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Abstract

Despite the presence of toll like receptor (TLR) expression in conventional $TCR{\alpha}{\beta}$ T cells, the direct role of TLR signaling via myeloid differentiation factor 88 (MyD88) within T lymphocytes on graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (allo-SCT) remains unknown. In the allo-SCT model of C57BL/6 ($H-2^b$) ${\rightarrow}$ B6D2F1 ($H-2^{b/d}$), recipients received transplants of wild type (WT) T-cell-depleted (TCD) bone marrow (BM) and splenic T cells from either WT or MyD88 deficient (MyD88KO) donors. Host-type ($H-2^d$) P815 mastocytoma or L1210 leukemia cells were injected either subcutaneously or intravenously to generate a GVHD/GVL model. Allogeneic recipients of MyD88KO T cells demonstrated a greater tumor growth without attenuation of GVHD severity. Moreover, GVHD-induced GVL effect, caused by increasing the conditioning intensity was also not observed in the recipients of MyD88KO T cells. In vitro, the absence of MyD88 in T cells resulted in defective cytolytic activity to tumor targets with reduced ability to produce IFN-${\gamma}$ or granzyme B, which are known to critical for the GVL effect. However, donor T cell expansion with effector and memory T-cell differentiation were more enhanced in GVHD hosts of MyD88KO T cells. Recipients of MyD88KO T cells experienced greater expansion of Foxp3- and IL4-expressing T cells with reduced INF-${\gamma}$ producing T cells in the spleen and tumor-draining lymph nodes early after transplantation. Taken together, these results highlight a differential role for MyD88 deficiency on donor T-cells, with decreased GVL effect without attenuation of the GVHD severity after experimental allo-SCT.

Keywords

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