title: Granzyme B produced by human plasmacytoid dendritic cells suppresses T-cell expansion.
abstract: Human plasmacytoid dendritic cells (pDCs) are crucially involved in the modulation of adaptive T-cell responses in the course of neoplastic, viral, and autoimmune disorders. In several of these diseases elevated extracellular levels of the serine protease granzyme B (GrB) are observed. Here we demonstrate that human pDCs can be an abundant source of GrB and that such GrB(+) pDCs potently suppress T-cell proliferation in a GrB-dependent, perforin-independent manner, a process reminiscent of regulatory T cells. Moreover, we show that GrB expression is strictly regulated on a transcriptional level involving Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), and STAT5 and that interleukin-3 (IL-3), a cytokine secreted by activated T cells, plays a central role for GrB induction. Moreover, we find that the immunosuppressive cytokine IL-10 enhances, while Toll-like receptor agonists and CD40 ligand strongly inhibit, GrB secretion by pDCs. GrB-secreting pDCs may play a regulatory role for immune evasion of tumors, antiviral immune responses, and autoimmune processes. Our results provide novel information about the complex network of pDC-T-cell interactions and may contribute to an improvement of prophylactic and therapeutic vaccinations.
authors: Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany.
authors: Bernd
authors: B
authors: Jahrsdörfer
authors: Angelika
authors: A
authors: Vollmer
authors: Sue E
authors: SE
authors: Blackwell
authors: Julia
authors: J
authors: Maier
authors: Kai
authors: K
authors: Sontheimer
authors: Thamara
authors: T
authors: Beyer
authors: Birgit
authors: B
authors: Mandel
authors: Oleg
authors: O
authors: Lunov
authors: Kyrylo
authors: K
authors: Tron
authors: G Ulrich
authors: GU
authors: Nienhaus
authors: Thomas
authors: T
authors: Simmet
authors: Klaus-Michael
authors: KM
authors: Debatin
authors: George J
authors: GJ
authors: Weiner
authors: Dorit
authors: D
authors: Fabricius
mesh_terms: D001171:Arthritis, Juvenile / Q000276:immunology* / Q000473:pathology; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D053804:Granzymes / Q000502:physiology*; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D007377:Interleukin-3; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C509213:GZMB protein, human; D053804:Granzymes