title: STAT3-silenced human dendritic cells have an enhanced ability to prime IFNγ production by both αβ and γδ T lymphocytes.
abstract: Dendritic cells (DC) are an attractive target for therapeutic manipulation of the immune system to enhance insufficient immune responses, such those occurring in cancer, or to dampen dangerous responses in allergic and autoimmune diseases. Main goal of this study was to manipulate human monocyte-derived DC (MDDC) function by silencing STAT3, since this transcription factor plays a key role as a negative regulator of immune surveillance, and is strongly involved in inflammation. STAT3 silencing did not affect the immunophenotype of both immature and toll-like receptor (TLR) ligand-matured DC. However, an altered cytokine secretion profile, characterized by lower IL10 and higher IL12 and TNFα levels, was observed in silenced DC with respect to control cells upon TLR triggering. Accordingly, STAT3 silenced MDDC promoted a higher IFNγ production by CD4(+) naïve T cells. Furthermore, STAT3 silencing in MDDC favored the activation of γδ T lymphocytes, an immune cell population with important antitumor effector activities. This effect was at least in part mediated by the increased IL12 production by silenced cells. STAT3 silencing also increased the levels of CCL4, a CCR5-binding chemokine known to be involved in T helper 1 (Th1) cell recruitment. Altogether these results strengthen the role of STAT3 as a critical check point of the suppression of Th1 responses, unraveling its potential to dampen DC capability to both induce and recruit different IFNγ producing T lymphocyte subsets.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sanseverino
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Purificato
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Varano
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Conti
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gessani
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome 00161, Italy. Electronic address: mariacristina.gauzzi@iss.it.
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Gauzzi
mesh_terms: D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D054407:Chemokine CCL4 / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D034622:RNA Interference; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism
chemical_list: D054407:Chemokine CCL4; D016207:Cytokines; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D050796:STAT3 Transcription Factor; D051193:Toll-Like Receptors; D018664:Interleukin-12; D007371:Interferon-gamma
keywords: Chemokine; Cytokine; Dendritic cell; RNA interference; STAT3; T helper