title: Graft-versus-host disease is independent of innate signaling pathways triggered by pathogens in host hematopoietic cells.
abstract: Graft-versus-host disease (GVHD) is initiated by APCs that prime alloreactive donor T cells. In antipathogen responses, Ag-bearing APCs receive signals through pattern-recognition receptors, including TLRs, which induce the expression of costimulatory molecules and production of inflammatory cytokines, which in turn mold the adaptive T cell response. However, in allogeneic hematopoietic stem cell transplantation (alloSCT), there is no specific pathogen, alloantigen is ubiquitous, and signals that induce APC maturation are undefined. To investigate APC activation in GVHD, we used recipient mice with hematopoietic cells genetically deficient in pathways critical for APC maturation in models in which host APCs are absolutely required. Strikingly, CD8-mediated and CD4-mediated GVHD were similar whether host APCs were wild-type or deficient in MyD88, TRIF, or MyD88 and TRIF, which excludes essential roles for TLRs and IL-1β, the key product of inflammasome activation. Th1 differentiation was if anything augmented when APCs were MyD88/TRIF(-/-), and T cell production of IFN-γ did not require host IL-12. GVHD was also intact when APCs lacked the type I IFNR, which amplifies APC activation pathways that induce type I IFNs. Thus in GVHD, alloreactive T cells can be activated when pathways critical for antipathogen T cell responses are impaired.
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Catherine
authors.initials: C
authors.lastname: Matte-Martone
authors.forename: Hung Sheng
authors.initials: HS
authors.lastname: Tan
authors.forename: Srividhya
authors.initials: S
authors.lastname: Venkatesan
authors.forename: Jennifer
authors.initials: J
authors.lastname: McNiff
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Demetris
authors.forename: Dhanpat
authors.initials: D
authors.lastname: Jain
authors.forename: Fadi
authors.initials: F
authors.lastname: Lakkis
authors.forename: David
authors.initials: D
authors.lastname: Rothstein
authors.forename: Warren D
authors.initials: WD
authors.lastname: Shlomchik
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000382:microbiology / Q000821:virology; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology; D006086:Graft vs Host Disease / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology*; D058507:Host Specificity / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011828:Radiation Chimera / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4