title: A critical role for the TLR4/TRIF pathway in allogeneic hematopoietic cell rejection by innate immune cells.
abstract: We show for the first time that signaling through the TLR4/TRIF pathway plays a critical role in allogeneic bone marrow cell (BMC) rejection. This appears to be unique to BMCs as organ allografts are rejected mainly via MyD88 signaling. Using T- or T-/B-cell-deficient mice, we found that BMC allorejection occurred early before T-cell activation and was T- and B-cell independent, suggesting an effector role for innate immune cells in BMC rejection. We further demonstrated the innate immune signaling in BMC allorejection by showing superior engraftment in mice deficient in TRIF or TLR4 but not in MyD88 or TLR3. The restored cytotoxicity in TRIF-deficient recipients transferred with wild-type F4/80(+) or NK1.1(+) cells suggests TRIF signaling dependence on macrophages or NK cells in early BMC rejection. Production of the proinflammatory cytokine IL-6 and TRIF relevant chemokine MCP-1 was significantly increased early after bone marrow transplantation. In vivo specific depletion of macrophages or NK innate immune cells in combination with anti-CD154/rapamycin resulted in additive-enhanced allogeneic engraftment. The requirement for irradiation was completely eliminated when both macrophages and NK cells were depleted in combination with anti-CD154/rapamycin to target T- and B-cells, supporting the hypothesis that two barriers involving innate and adaptive immunity exist in mediating the rejection of allogeneic BMCs. In summary, our results clearly demonstrate a previously unappreciated role for innate immunity in BMC allorejection via signaling through a unique MyD88-independent TLR4/TRIF mechanism. These findings may have direct clinical impact on strategies for conditioning recipients for stem cell transplantation.
authors.affiliation: Institute for Cellular Therapeutics, University of Louisville, Louisville, KY, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Zhu
authors.forename: Lala-Rukh
authors.initials: LR
authors.lastname: Hussain
authors.forename: Yiming
authors.initials: Y
authors.lastname: Huang
authors.forename: Chuanlin
authors.initials: C
authors.lastname: Ding
authors.forename: Larry D
authors.initials: LD
authors.lastname: Bozulic
authors.forename: Yujie
authors.initials: Y
authors.lastname: Wen
authors.forename: Suzanne T
authors.initials: ST
authors.lastname: Ildstad
mesh_terms: D056704:Adaptive Immunity; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D004002:Clodronic Acid / Q000494:pharmacology; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D014184:Transplantation, Homologous
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D004002:Clodronic Acid; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D020123:Sirolimus; D051196:Toll-Like Receptor 3; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse