title: CD70 signaling is critical for CD28-independent CD8+ T cell-mediated alloimmune responses in vivo.
abstract: The inability to reproducibly induce robust and durable transplant tolerance using CD28-B7 pathway blockade is in part related to the persistence of alloreactive effector/memory CD8(+) T cells that are less dependent on this pathway for their cellular activation. We studied the role of the novel T cell costimulatory pathway, CD27-CD70, in alloimmunity in the presence and absence of CD28-B7 signaling. CD70 blockade prolonged survival of fully mismatched vascularized cardiac allografts in wild-type murine recipients, and in CD28-deficient mice induced long-term survival while significantly preventing the development of chronic allograft vasculopathy. CD70 blockade had little effect on CD4(+) T cell function but prevented CD8(+) T cell-mediated rejection, inhibited the proliferation and activation of effector CD8(+) T cells, and diminished the expansion of effector and memory CD8(+) T cells in vivo. Thus, the CD27-CD70 pathway is critical for CD28-independent effector/memory CD8(+) alloreactive T cell activation in vivo. These novel findings have important implications for the development of transplantation tolerance-inducing strategies in primates and humans, in which CD8(+) T cell depletion is currently mandatory.
authors.affiliation: Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Yamada
authors.forename: Alan D
authors.initials: AD
authors.lastname: Salama
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sho
authors.forename: Nader
authors.initials: N
authors.lastname: Najafian
authors.forename: Toshiro
authors.initials: T
authors.lastname: Ito
authors.forename: John P
authors.initials: JP
authors.lastname: Forman
authors.forename: Reshma
authors.initials: R
authors.lastname: Kewalramani
authors.forename: Sigrid
authors.initials: S
authors.lastname: Sandner
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
authors.forename: Michael R
authors.initials: MR
authors.lastname: Clarkson
authors.forename: Didier A
authors.initials: DA
authors.lastname: Mandelbrot
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Hideo
authors.initials: H
authors.lastname: Oshima
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Geetha
authors.initials: G
authors.lastname: Chalasani
authors.forename: Fadi G
authors.initials: FG
authors.lastname: Lakkis
authors.forename: Hugh
authors.initials: H
authors.lastname: Auchincloss
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology*; D053282:CD27 Ligand; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D015536:Down-Regulation / Q000276:immunology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D007518:Isoantibodies / Q000096:biosynthesis / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D016042:Transplantation, Heterotopic / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D053282:CD27 Ligand; D018106:CD28 Antigens; C505772:Cd70 protein, mouse; D007518:Isoantibodies; D008565:Membrane Proteins; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7