title: Differential regulation of naïve and memory CD4+ T cells by alternatively activated dendritic cells.
abstract: Promising immunotherapeutic tools for T cell-mediated pathologies are alternatively activated dendritic cells (aaDC), which exert their effect through the regulation and tolerization of T cells. As naïve and memory T cells have different susceptibilities to tolerogenic signals, it is important to understand the modulatory effects of aaDC on these T cell subsets. We have examined regulation of naïve and memory CD4+ T cells by human aaDC generated with dexamethasone, the active form of vitamin D3, 1alpha,25-dihydroxyvitamin D3, and LPS. Although aaDC induced low, primary, allogeneic responses by naïve and memory T cells, aaDC regulated the differentiation of these T cell subsets in a distinct manner. Naïve T cells primed by aaDC retained a strong, proliferative capacity upon restimulation but were skewed toward a low IFN-gamma/high IL-10 cytokine profile. In contrast, memory T cells primed by aaDC became hyporesponsive in terms of proliferation and cytokine production. Induction of anergy in memory T cells by aaDC was not a result of the presence of CD25hi regulatory T cells and could be partially reversed by IL-2. Both T cell subsets acquired regulatory activity and inhibited primary CD4 and CD8 responses. Addition of exogenous IL-12p70 during T cell priming by aaDC prevented anergy induction in memory T cells and cytokine polarization in naïve T cells, indicating that the lack of IL-12p70 is a key feature of aaDC. Our finding that aaDC differentially regulate naïve and memory T cells is important for understanding and maximizing the therapeutic potential of aaDC.
authors.affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine, 4th Floor Catherine Cookson Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Anderson
authors.forename: Bethan L
authors.initials: BL
authors.lastname: Sayers
authors.forename: Muzlifah A
authors.initials: MA
authors.lastname: Haniffa
authors.forename: David J
authors.initials: DJ
authors.lastname: Swan
authors.forename: Julie
authors.initials: J
authors.lastname: Diboll
authors.forename: Xiao-Nong
authors.initials: XN
authors.lastname: Wang
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
authors.forename: Catharien M U
authors.initials: CM
authors.lastname: Hilkens
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects; D054415:Chemokine CCL19 / Q000494:pharmacology; D045142:Cross-Priming / Q000187:drug effects; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology*; D007249:Inflammation; D018664:Interleukin-12 / Q000096:biosynthesis; D008024:Ligands; D010641:Phenotype; D054400:Receptors, CCR7 / Q000378:metabolism
chemical_list: C515460:CCL19 protein, human; C515370:CCR7 protein, human; D054415:Chemokine CCL19; D016207:Cytokines; D008024:Ligands; D054400:Receptors, CCR7; D018664:Interleukin-12