title: IL-1 Receptor Signaling on Graft Parenchymal Cells Regulates Memory and De Novo Donor-Reactive CD8 T Cell Responses to Cardiac Allografts.
abstract: Reperfusion of organ allografts induces a potent inflammatory response that directs rapid memory T cell, neutrophil, and macrophage graft infiltration and their activation to express functions mediating graft tissue injury. The role of cardiac allograft IL-1 receptor (IL-1R) signaling in this early inflammation and the downstream primary alloimmune response was investigated. When compared with complete MHC-mismatched wild-type cardiac allografts, IL-1R(-/-) allografts had marked decreases in endogenous memory CD8 T cell and neutrophil infiltration and expression of proinflammatory mediators at early times after transplant, whereas endogenous memory CD4 T cell and macrophage infiltration was not decreased. IL-1R(-/-) allograft recipients also had marked decreases in de novo donor-reactive CD8, but not CD4, T cell development to IFN-γ-producing cells. CD8 T cell-mediated rejection of IL-1R(-/-) cardiac allografts took 3 wk longer than wild-type allografts. Cardiac allografts from reciprocal bone marrow reconstituted IL-1R(-/-)/wild-type chimeric donors indicated that IL-1R signaling on graft nonhematopoietic-derived, but not bone marrow-derived, cells is required for the potent donor-reactive memory and primary CD8 T cell alloimmune responses observed in response to wild-type allografts. These studies implicate IL-1R-mediated signals by allograft parenchymal cells in generating the stimuli-provoking development and elicitation of optimal alloimmune responses to the grafts.
authors: Department of Immunology, Cleveland Clinic, Cleveland, OH 44195; Division of Immunobiology, Research Institute for Biological Science, Science University of Tokyo, Chiba 278-8510, Japan; Department of Urology, Tokyo Women's Medical University, Tokyo 162-0054, Japan;
authors: Shoichi
authors: http://orcid.org/0000-0003-4300-1495
authors: S
authors: Iida
authors: Department of Immunology, Cleveland Clinic, Cleveland, OH 44195; Department of Urology, Osaka University School of Medicine, Osaka 565-0871, Japan; and.
authors: Hidetoshi
authors: H
authors: Tsuda
authors: Department of Immunology, Cleveland Clinic, Cleveland, OH 44195;
authors: Toshiaki
authors: T
authors: Tanaka
authors: Department of Immunology, Cleveland Clinic, Cleveland, OH 44195;
authors: Danielle D
authors: DD
authors: Kish
authors: Department of Immunology, Cleveland Clinic, Cleveland, OH 44195; Department of Urology, Osaka University School of Medicine, Osaka 565-0871, Japan; and.
authors: Toyofumi
authors: http://orcid.org/0000-0002-3345-9294
authors: T
authors: Abe
authors: Department of Immunology, Cleveland Clinic, Cleveland, OH 44195; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors: Charles A
authors: CA
authors: Su
authors: Division of Immunobiology, Research Institute for Biological Science, Science University of Tokyo, Chiba 278-8510, Japan; Department of Urology, Tokyo Women's Medical University, Tokyo 162-0054, Japan;
authors: Ryo
authors: http://orcid.org/0000-0002-8008-3410
authors: R
authors: Abe
authors: Division of Immunobiology, Research Institute for Biological Science, Science University of Tokyo, Chiba 278-8510, Japan; Department of Urology, Tokyo Women's Medical University, Tokyo 162-0054, Japan;
authors: Kazunari
authors: K
authors: Tanabe
authors: Department of Immunology, Cleveland Clinic, Cleveland, OH 44195;
authors: Anna
authors: A
authors: Valujskikh
authors: Department of Immunology, Cleveland Clinic, Cleveland, OH 44195; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors: William M
authors: WM
authors: Baldwin
authors: Department of Immunology, Cleveland Clinic, Cleveland, OH 44195; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106 fairchr@ccf.org.
authors: Robert L
authors: RL
authors: Fairchild
mesh_terms: D064591:Allografts / Q000378:metabolism*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D006084:Graft Rejection / Q000235:genetics; D016027:Heart Transplantation; D007156:Immunologic Memory / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D007519:Isoantigens; D017472:Receptors, Interleukin-1; D007371:Interferon-gamma