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

Abstract

• 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.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 1 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-a 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 1 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. (Blood. 2013;121(16):3103-3111)

Dendritic cell recruitment and activation in autoimmunity

“…2). In addition, we and others have shown that pDCs secrete high amounts of GrB when exposed to IL-21 [239,240], a Th17-cytokine that is strongly expressed in lesional skin of LE patients [241]. Because pDCs do not express perforin [242], a cytotoxic role for pDC-derived GrB remained uncertain.…”

Are all granzymes cytotoxicin vivo?

“…IL-21 seems to be important for granzyme expression in different cell types, such as B cells (Hagn et al, 2009) and plasmacytoid dendritic cells (Karrich et al, 2013). The expression of granzymes in some cells is controversial: for example in neutrophils reviewed in (Susanto et al, 2012) or human polymorphonuclear leukocytes .…”

Granzymes Regulate Proinflammatory Cytokine Responses

“…In mDCs, no constitutive GrB protein expression is reported, but GrB and perforin protein expression can be induced by treatment with TLR7 and TLR8 agonists (59). In contrast, TLR7 and TLR9 agonists inhibit GrB protein expression in pDCs (57)(58)(59)(60).…”

“…There is ample evidence that both human mye-loid dendritic cells (mDCs) and human plasmacytoid DCs (pDCs) express GrB (56)(57)(58)(59)(60). Constitutive mRNA and protein expression has been found in pDCs (57,60), whereas IL-3, IL-10, and IL-21 upregulate GrB mRNA and protein expression in these cells (57,58,60). In mDCs, no constitutive GrB protein expression is reported, but GrB and perforin protein expression can be induced by treatment with TLR7 and TLR8 agonists (59).…”