title: Tolerogenic dendritic cells impede priming of naïve CD8⁺ T cells and deplete memory CD8⁺ T cells.
abstract: Type 1 diabetes is a T-cell-mediated autoimmune disease in which autoreactive CD8(+)  T cells destroy the insulin-producing pancreatic beta cells. Vitamin D3 and dexamethasone-modulated dendritic cells (Combi-DCs) loaded with islet antigens inducing islet-specific regulatory CD4(+)  T cells may offer a tissue-specific intervention therapy. The effect of Combi-DCs on CD8(+)  T cells, however, remains unknown. To investigate the interaction of CD8(+)  T cells with Combi-DCs presenting epitopes on HLA class I, naive, and memory CD8(+)  T cells were co-cultured with DCs and proliferation and function of peptide-specific T cells were analyzed. Antigen-loaded Combi-DCs were unable to prime naïve CD8(+)  T cells to proliferate, although a proportion of T cells converted to a memory phenotype. Moreover, expansion of CD8(+)  T cells that had been primed by mature monocyte-derived DCs (moDCs) was curtailed by Combi-DCs in co-cultures. Combi-DCs expanded memory T cells once, but CD8(+)  T-cell numbers collapsed by subsequent re-stimulation with Combi-DCs. Our data point that (re)activation of CD8(+)  T cells by antigen-pulsed Combi-DCs does not promote, but rather deteriorates, CD8(+)  T-cell immunity. Yet, Combi-DCs pulsed with CD8(+)  T-cell epitopes also act as targets of cytotoxicity, which is undesirable for survival of Combi-DCs infused into patients in therapeutic immune intervention strategies.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Fleur S
authors.initials: FS
authors.lastname: Kleijwegt
authors.forename: Diahann T S L
authors.initials: DT
authors.lastname: Jansen
authors.forename: Josefine
authors.initials: J
authors.lastname: Teeler
authors.forename: Antoinette M
authors.initials: AM
authors.lastname: Joosten
authors.forename: Sandra
authors.initials: S
authors.lastname: Laban
authors.forename: Tatjana
authors.initials: T
authors.lastname: Nikolic
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000276:immunology; D017637:Clonal Deletion; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation*; D003907:Dexamethasone / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D002762:Cholecalciferol; D003907:Dexamethasone