title: CTLA-4 is expressed by human monocyte-derived dendritic cells and regulates their functions.
abstract: Cytotoxic T lymphocyte antigen-4 (CTLA-4) is the major negative regulator of T-cell responses, although growing evidence supports its wider role as an immune attenuator that may also act in other cell lineages. Here, we have analyzed the expression of CTLA-4 in human monocytes and monocyte-derived dendritic cells (DCs), and the effect of its engagement on cytokine production and T-cell stimulatory activity by mature DCs. CTLA-4 was highly expressed on freshly isolated monocytes, then down-modulated upon differentiation toward immature DCs (iDCs) and it was markedly upregulated on mature DCs obtained with different stimulations (lipopolysaccharides [LPS], Poly:IC, cytokines). In line with the functional role of CTLA-4 in T cells, treatment of mDCs with an agonistic anti-CTLA-4 mAb significantly enhanced secretion of regulatory interleukin (IL)-10 but reduced secretion of IL-8/IL-12 pro-inflammatory cytokines, as well as autologous CD4+ T-cell proliferation in response to stimulation with recall antigen purified protein derivative (PPD) loaded-DCs. Neutralization of IL-10 with an anti-IL-10 antibody during the mDCs-CD4+ T-cell co-culture partially restored the ability of anti-CTLA-4-treated mDCs to stimulate T-cell proliferation in response to PPD. Taken together, our data provide the first evidence that CTLA-4 receptor is expressed by human monocyte-derived mDCs upon their full activation and that it exerts immune modulatory effects.
authors.affiliation: Department of Hematology and Oncology, University of Genoa, Genoa, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Laurent
authors.forename: Paolo
authors.initials: P
authors.lastname: Carrega
authors.forename: Daniele
authors.initials: D
authors.lastname: Saverino
authors.forename: Patrizia
authors.initials: P
authors.lastname: Piccioli
authors.forename: Marta
authors.initials: M
authors.lastname: Camoriano
authors.forename: Anna
authors.initials: A
authors.lastname: Morabito
authors.forename: Beatrice
authors.initials: B
authors.lastname: Dozin
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Fontana
authors.forename: Rita
authors.initials: R
authors.lastname: Simone
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Mortara
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Mingari
authors.forename: Guido
authors.initials: G
authors.lastname: Ferlazzo
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Pistillo
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D056747:Immunomodulation; D008213:Lymphocyte Activation; D009000:Monocytes / Q000473:pathology*; D014373:Tuberculin / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; D014373:Tuberculin