IL-21–stimulated human plasmacytoid dendritic cells secrete granzyme B, which impairs their capacity to induce T-cell proliferation

• Published in: Blood Vol. 121; no. 16; pp. 3103 - 3111
• Main Authors: Karrich, Julien J., Jachimowski, Loes C.M., Nagasawa, Maho, Kamp, Angela, Balzarolo, Melania, Wolkers, Monika C., Uittenbogaart, Christel H., Marieke van Ham, S., Blom, Bianca
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.04.2013; American Society of Hematology
• Subjects: CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; Cell Proliferation; Cell Survival; Cells, Cultured; Child, Preschool; Cytokines - immunology; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Granzymes - genetics; Granzymes - immunology; Humans; Immunobiology; Interleukins - immunology; Toll-Like Receptors - immunology; Up-Regulation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-08-452995

Plasmacytoid dendritic cells (pDCs) play a crucial role during innate immunity by secreting bulk amounts of type I interferons (IFNs) in response to Toll-like receptor (TLR)–mediated pathogen recognition. In addition, pDCs can also contribute to adaptive immunity by activation of antigen-specific T cells. Furthermore, it is well established that pDCs contribute to the pathogenesis of autoimmune diseases, including lupus. Interleukin-21 (IL-21) is a cytokine produced by activated CD4+ T and natural killer T (NKT) cells and has a pleiotropic role in immunity by controlling myeloid DC-, NKT-, T-, and B-cell functions. It has remained elusive whether IL-21 affects pDCs. Here we investigate the role of IL-21 in human pDC activation and function and observe that IL-21 activates signal transducer and activator of transcription 3 in line with the finding that pDCs express the IL-21 receptor. Although IL-21 did not affect TLR-induced type I IFNs, IL-6, and TNF-α nor expression of major-histocompatibility-complex class II or costimulatory molecules, IL-21 markedly increased expression of the serine protease granzyme B (GrB). We demonstrate that GrB induction was, in part, responsible for IL-21-mediated downmodulation of CD4+ T-cell proliferation induced by TLR preactivated pDCs. Collectively, our data provide evidence that pDCs are important cells to consider when investigating the role of IL-21 in immunity or pathogenesis. •pDCs functionally express the IL-21 receptor and produce granzyme B in response to IL-21.•IL-21–induced granzyme B in pDC impairs pDC's capacity to induce T-cell proliferation.