title: CD40Ig treatment results in allograft acceptance mediated by CD8CD45RC T cells, IFN-gamma, and indoleamine 2,3-dioxygenase.
abstract: Treatment with CD40Ig results in indefinite allograft survival in a complete MHC-mismatched heart allograft model in the rat. Here we show that serial second, third, and fourth adoptive transfers of total splenocytes from CD40Ig-treated recipients into secondary recipients led to indefinite donor-specific allograft acceptance. Purification of splenocyte subpopulations from CD40Ig-treated recipients demonstrated that only the adoptively transferred CD8(+)CD45RC(low) subset resulted in donor-specific long-term survival, whereas CD8(+)CD45RC(low) T cells from naive animals did not. Accepted grafts displayed increased indoleamine 2,3-dioxygenase (IDO) expression restricted in the graft to ECs. Coculture of donor ECs with CD8(+)CD45RC(low) T cells purified from CD40Ig-treated animals resulted in donor-specific IDO expression dependent on IFN-gamma. Neutralization of IFN-gamma or IDO triggered acute allograft rejection in both CD40Ig-treated and adoptively transferred recipients. This study demonstrates for what we believe to be the first time that interference in CD40-CD40 ligand (CD40-CD40L) interactions induces allospecific CD8(+) Tregs that maintain allograft survival. CD8(+)CD45RC(low) T cells act through IFN-gamma production, which in turn induces IDO expression by graft ECs. Thus, donor alloantigen-specific CD8(+) Tregs may promote local graft immune privilege through IDO expression.
authors.affiliation: INSERM U643, Centre Hopitalier Universitaire de Nantes, Institut de Transplantation et de Recherche en Transplantation (ITERT), and Université de Nantes, Faculté de Médecine, Nantes, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Guillonneau
authors.forename: Marcelo
authors.initials: M
authors.lastname: Hill
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Hubert
authors.forename: Elise
authors.initials: E
authors.lastname: Chiffoleau
authors.forename: Caroline
authors.initials: C
authors.lastname: Hervé
authors.forename: Xian-Liang
authors.initials: XL
authors.lastname: Li
authors.forename: Michèle
authors.initials: M
authors.lastname: Heslan
authors.forename: Claire
authors.initials: C
authors.lastname: Usal
authors.forename: Laurent
authors.initials: L
authors.lastname: Tesson
authors.forename: Séverine
authors.initials: S
authors.lastname: Ménoret
authors.forename: Abdelhadi
authors.initials: A
authors.lastname: Saoudi
authors.forename: Brigitte
authors.initials: B
authors.lastname: Le Mauff
authors.forename: Régis
authors.initials: R
authors.lastname: Josien
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Cuturi
authors.forename: Ignacio
authors.initials: I
authors.lastname: Anegon
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D016027:Heart Transplantation / Q000276:immunology / Q000502:physiology*; D007108:Immune Tolerance / Q000187:drug effects; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: C499839:CD40Ig protein, recombinant; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma