title: A novel alloantigen-specific CD8+PD1+ regulatory T cell induced by ICOS-B7h blockade in vivo.
abstract: Delayed ICOS-B7h signal blockade promotes significant prolongation of cardiac allograft survival in wild-type but not in CD8-deficient C57BL/6 recipients of fully MHC-mismatched BALB/c heart allografts, suggesting the possible generation of CD8(+) regulatory T cells in vivo. We now show that the administration of a blocking anti-ICOS mAb results in the generation of regulatory CD8(+) T cells. These cells can transfer protection and prolong the survival of donor-specific BALB/c, but not third party C3H, heart grafts in CD8-deficient C57BL/6 recipients. This is unique to ICOS-B7h blockade, because B7 blockade by CTLA4-Ig prolongs graft survival in CD8-deficient mice and does not result in the generation of regulatory CD8(+) T cells. Those cells localize to the graft, produce both IFN-gamma and IL-4 after allostimulation in vitro, prohibit the expansion of alloreactive CD4(+) T cells, and appear to mediate a Th2 switch of recipient CD4(+) T cells after adoptive transfer in vivo. Finally, these cells are not confined to the CD28-negative population but express programmed death 1, a molecule required for their regulatory function in vivo. CD8(+)PD1(+) T cells suppress alloreactive CD4(+) T cells but do not inhibit the functions by alloreactive CD8(+) T cells in vitro. These results describe a novel allospecific regulatory CD8(+)PD1(+) T cell induced by ICOS-B7h blockade in vivo.
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Izawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamaura
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Albin
authors.forename: Mollie
authors.initials: M
authors.lastname: Jurewicz
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tanaka
authors.forename: Michael R
authors.initials: MR
authors.lastname: Clarkson
authors.forename: Takuya
authors.initials: T
authors.lastname: Ueno
authors.forename: Antje
authors.initials: A
authors.lastname: Habicht
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Reza
authors.initials: R
authors.lastname: Abdi
authors.forename: Todd
authors.initials: T
authors.lastname: Pearson
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Nader
authors.initials: N
authors.lastname: Najafian
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005434:Flow Cytometry; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D060945:Inducible T-Cell Co-Stimulator Ligand; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D011506:Proteins / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D007519:Isoantigens; D011506:Proteins