IL-21 may promote Granzyme B-dependent NK/plasmacytoid dendritic cell functional interaction in cutaneous lupus erythematosus

Autoimmune skin lesions are characterized by a complex cytokine milieu and by the accumulation of plasmacytoid dendritic cells (pDCs). Granzyme B (GrB) transcript is abundant in activated pDCs, though its mechanisms of regulation and biological role are largely unknown. Here we report that IL-21 was the only Th1/Th17 cytokine able to induce the expression and secretion of GrB by pDCs and that this action was counteracted by the autocrine production of type I interferons (IFNs). In lupus erythematosus (LE) skin lesions, the percentage of GrB(+) pDCs directly correlated with the IL-21/MxA ratio, indicating that the interplay between these two cytokines finely tune the levels of pDC-dependent GrB also in vivo. In LE, pDCs colocalized with professional cytotoxic cells at sites of epithelial damage, suggesting a role in keratinocyte killing. In accordance, we demonstrate that supernatants of IL-21-activated pDCs promoted autologous keratinocyte killing by NK cells and this action was dependent on GrB. These results propose a GrB-dependent functional interaction between pDCs and NK cells and highlight a negative feedback regulation by type I IFNs in vitro and in vivo that may function to limit excessive tissue damage.