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 T helper 1/T helper 17 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 IFNs. In lupus erythematosus skin lesions, the percentage of GrB+pDCs directly correlated with the IL-21/MxA ratio, indicating that the interplay between these two cytokines finely tunes the levels of pDC-dependent GrB also in vivo. In lupus erythematosus, pDCs colocalized with professional cytotoxic cells at sites of epithelial damage, suggesting a role in keratinocyte killing. Accordingly, we demonstrate that supernatants of IL-21-activated pDCs promoted autologous keratinocyte killing by natural killer cells and this action was dependent on GrB. These results propose a GrB-dependent functional interaction between pDCs and natural killer cells and highlight a negative feedback regulation by type I IFNs in vitro and in vivo that may function to limit excessive tissue damage.
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Valentina
V
Salvi
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
William
W
Vermi
National Institute for Health, Migration and Poverty (NIHMP), Rome, Italy.
Andrea
A
Cavani
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Silvia
S
Lonardi
Laboratory of Experimental Immunology, Istituto Dermopatico dell'Immacolata, Rome, Italy.
Teresa
T
Carbone
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Fabio
F
Facchetti
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Daniela
D
Bosisio
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Humanitas Clinical and Research Center, Rozzano, Italy. Electronic address: silvano.sozzani@unibs.it.
Silvano
S
Sozzani
D017209:Apoptosis; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D053804:Granzymes / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007378:Interleukins / Q000378:metabolism*; D015603:Keratinocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology*; D008178:Lupus Erythematosus, Cutaneous / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000098546:Interleukin-21
D016207:Cytokines; D007378:Interleukins; D053804:Granzymes; D000098546:Interleukin-21