title: Myeloma cells act as tolerogenic antigen-presenting cells and induce regulatory T cells in vitro.
abstract: Regulatory T cells (Tregs) are essential for maintenance of self-tolerance; however, tumor cells can exploit the tolerance to escape the immune system. We investigated the Tregs frequency in patients with multiple myeloma (MM) and in those with monoclonal gammopathy of undetermined significance (MGUS), and found that CD4(+) FoxP3(+) and CD8(+) FoxP3(+) Tregs were significantly increased in patients with MM and correlated with the active phase. Both Tregs subsets were expanded in cocultures of CD3(+) lymphocytes and fresh CD138(+) MM plasma cells or RPMI8226 and U266 cell lines and functioned as natural (n) and inducible (i) Tregs insofar as they inhibited the proliferation of stimulated CD3 lymphocytes via contact-dependent and contact-independent pathways. Induction of Tregs by MM plasma cells required a contact-dependent pathway, implying antigen recognition by T cells. MM plasma cells acted as immature and tolerogenic antigen-presenting cells (APCs), in that they displayed low CD80/CD86 expression associated with a phagocytic activity. By acting as immature APCs, MM plasma cells plausibly expand (n)Tregs and (i)Tregs both through conversion of CD3(+) FoxP3(-) into CD3(+) FoxP3(+) T cells and proliferation of CD3(+) FoxP3(+) T cells, which may suppress the anti-MM immune response.
authors.affiliation: General Pathology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Maria Antonia
authors.initials: MA
authors.lastname: Frassanito
authors.affiliation: Department of Human Anatomy, Histology and Embryology, University of Bari Medical School, Bari, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Ruggieri
authors.affiliation: Section of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Desantis
authors.affiliation: Section of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marzo
authors.affiliation: Section of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Leone
authors.affiliation: Section of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Racanelli
authors.affiliation: General Pathology Unit, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Ruggiero
authors.initials: R
authors.lastname: Fumarulo
authors.affiliation: Section of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Dammacco
authors.affiliation: Section of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Vacca
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000473:pathology; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002450:Cell Communication; D049109:Cell Proliferation; D018920:Coculture Techniques; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007108:Immune Tolerance; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010950:Plasma Cells / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D053668:Syndecan-1 / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: D017252:CD3 Complex; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508241:SDC1 protein, human; D053668:Syndecan-1
keywords: antigen-presenting cells; multiple myeloma; regulatory T cells