CTLA-4 is expressed by human monocyte—derived dendritic cells and regulates their functions

• Published in: Human immunology 2010-10, Vol.71 (10), p.934-941
• Main Authors: Laurent, Stefania, Carrega, Paolo, Saverino, Daniele, Piccioli, Patrizia, Camoriano, Marta, Morabito, Anna, Dozin, Beatrice, Fontana, Vincenzo, Simone, Rita, Mortara, Lorenzo, Mingari, Maria Cristina, Ferlazzo, Guido, Pistillo, Maria Pia
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Antibodies, Monoclonal - pharmacology; Antigens, CD - immunology; Antigens, CD - metabolism; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; Cell Differentiation - immunology; Cell Proliferation; Cells, Cultured; CTLA-4; CTLA-4 Antigen; Cytokine secretion; Cytokines - genetics; Cytokines - immunology; Cytokines - metabolism; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dendritic Cells - pathology; Gene Expression Regulation - immunology; Humans; Immunomodulation; Lymphocyte Activation; Monocytes - pathology; T-cell proliferation; Tuberculin - immunology; Tuberculin - metabolism
• ISSN: 0198-8859; 1879-1166
• DOI: 10.1016/j.humimm.2010.07.007

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.