Granzyme B produced by human plasmacytoid dendritic cells suppresses T-cell expansion.
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.
Jahrsdörfer
Bernd
B
Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany.
Vollmer
Angelika
A
Blackwell
Sue E
SE
Maier
Julia
J
Sontheimer
Kai
K
Beyer
Thamara
T
Mandel
Birgit
B
Lunov
Oleg
O
Tron
Kyrylo
K
Nienhaus
G Ulrich
GU
Simmet
Thomas
T
Debatin
Klaus-Michael
KM
Weiner
George J
GJ
Fabricius
Dorit
D
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*
D007377:Interleukin-3; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C509213:GZMB protein, human; D053804:Granzymes