title: Tolerogenic dendritic cells generated with different immunosuppressive cytokines induce antigen-specific anergy and regulatory properties in memory CD4+ T cells.
abstract: Dendritic cells (DCs) are professional APCs involved in the initiation of both immunity and immunological tolerance. In autoimmune diseases or graft rejections, most reactive lymphocytes are effector/memory cells. It is believed that memory T cells are more resistant to tolerance induction than naive lymphocytes; however, studies on mechanisms for their efficient tolerization are still scarce. In this study, we generated human monocyte-derived DCs by culture with GM-CSF and IL-4 (control DCs), as well as tolerogenic DCs (tDCs) by adding IL-10, IL-10/TGF-beta1, or IL-10/IL-6. Cells were maturated with TNF-alpha/PGE(2). Compared with control DCs, tDCs had similar expression of HLA-DR, CD80, and CD86, lower expression of CD40, higher levels of macrophage markers, enhanced endocytic ability, increased secretion of IL-6, IL-10 (only tDCs generated with IL-10 and tDCs generated with IL-10/IL-6), and PGE(2), and lower secretion of IL-12 and IL-23. In vitro, tDCs had the capacity to induce anergy in tetanus toxoid-specific memory CD4(+) T cells, whereas the proliferative response to an unrelated Ag was intact. Anergy could be reverted upon exposure to IL-2. tDC-primed T cells have low suppressive ability. Nevertheless, the generation of both anergic and regulatory T cells was more efficient with tDCs generated with IL-10/TGF-beta1. Microarray-based gene expression profiling reflected modulated expression of several transcripts in tDCs. Surface CLIP-HLA-DR complexes and intracellular thrombospondin-1 were increased in the three tDCs. CD39 was highly expressed only in tDC-TGF, which correlated with increased adenosine production. We propose that these molecules, together with IL-10 and prostanoids, are key factors to induce Ag-specific tolerance in memory T cells.
authors.affiliation: Department of Molecular Biomedicine, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico.
authors.forename: Honorio
authors.initials: H
authors.lastname: Torres-Aguilar
authors.forename: Sergio R
authors.initials: SR
authors.lastname: Aguilar-Ruiz
authors.forename: Gabriela
authors.initials: G
authors.lastname: González-Pérez
authors.forename: Rosario
authors.initials: R
authors.lastname: Munguía
authors.forename: Sandra
authors.initials: S
authors.lastname: Bajaña
authors.forename: Marco A
authors.initials: MA
authors.lastname: Meraz-Ríos
authors.forename: Carmen
authors.initials: C
authors.lastname: Sánchez-Torres
mesh_terms: D000944:Antigens, Differentiation, B-Lymphocyte / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology; D016207:Cytokines / Q000502:physiology*; D003713:Dendritic Cells / Q000145:classification / Q000276:immunology* / Q000378:metabolism*; D015232:Dinoprostone / Q000502:physiology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000502:physiology; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016753:Interleukin-10 / Q000502:physiology; D008264:Macrophages / Q000145:classification / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D019700:Thrombospondin 1 / Q000502:physiology
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; C508609:IL10 protein, human; D007166:Immunosuppressive Agents; D019700:Thrombospondin 1; C045084:invariant chain; D016753:Interleukin-10; D015232:Dinoprostone