title: Dendritic cell type determines the mechanism of bystander suppression by adaptive T regulatory cells specific for the minor antigen HA-1.
abstract: One hallmark of acquired tolerance is bystander suppression, a process whereby Ag-specific (adaptive) T regulatory cells (TR) inhibit the T effector cell response both to specific Ag and to a colocalized third-party Ag. Using peripheral blood T cells from recipients of HLA-identical kidney transplants as responders in the trans vivo-delayed type hypersensitivity assay, we found that dendritic cells (DC), but not monocyte APCs, could mediate bystander suppression of EBV-specific recall response. When HA-1(H) peptide was added to mixtures of plasmacytoid DC (pDC) and T cells, bystander suppression of the response to a colocalized recall Ag occurred primarily via indolamine-2,3-dioxygenase (IDO) production. Similarly, addition of HA-1(H) peptide to cocultures of T cells and pDC, but not myeloid DC (mDC), induced IDO activity in vitro. When mDC presented HA-1(H) peptide to Ag-specific CD8+ TR, cytokine release (TGF-beta, IL-10, or both) was the primary mode of bystander suppression. Bystander suppression via mDC was reversed not only by Ab to TGF-beta and its receptor on T cells, but also by Ab to thrombospondin-1. EBV addition did not induce IDO or thrombospondin-1 in T-DC cocultures, suggesting that these DC products are not induced by T effector cells, but only by TR cells. These results shed light upon the mechanism of bystander suppression by donor Ag-specific TR in patients with organ transplant tolerance and underscores the distinct and critical roles of mDC and pDCs in this phenomenon.
authors.affiliation: Department of Surgery, University of Wisconsin, Madison, WI 53792, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Derks
authors.forename: Ewa
authors.initials: E
authors.lastname: Jankowska-Gan
authors.forename: Qingyong
authors.initials: Q
authors.lastname: Xu
authors.forename: William J
authors.initials: WJ
authors.lastname: Burlingham
mesh_terms: D000222:Adaptation, Physiological / Q000276:immunology; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D024201:Bystander Effect / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D045142:Cross-Priming / Q000276:immunology; D003713:Dendritic Cells / Q000145:classification* / Q000166:cytology / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000517:prevention & control; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D016030:Kidney Transplantation / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D015778:Minor Histocompatibility Antigens / Q000276:immunology* / Q000378:metabolism; D009842:Oligopeptides / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*