title: 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.
abstract: Despite the presence of toll like receptor (TLR) expression in conventional TCRαβ 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)) → 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-γ 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-γ 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.
authors.affiliation: Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Lim
authors.affiliation: Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Da-Bin
authors.initials: DB
authors.lastname: Ryu
authors.affiliation: Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Department of Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Gyeongsin
authors.initials: G
authors.lastname: Park
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Chang-Ki
authors.initials: CK
authors.lastname: Min
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D006086:Graft vs Host Disease / Q000276:immunology*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88
keywords: GVHD; GVL effect; MyD88; T cell; Treg and allo-SCT