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J Invest Dermatol. 2017 Jul;137(7):1493-1500. doi: 10.1016/j.jid.2017.03.016. Epub 2017 Mar 23.

IL-21 May Promote Granzyme B-Dependent NK/Plasmacytoid Dendritic Cell Functional Interaction in Cutaneous Lupus Erythematosus.

Author information

1
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
2
National Institute for Health, Migration and Poverty (NIHMP), Rome, Italy.
3
Laboratory of Experimental Immunology, Istituto Dermopatico dell'Immacolata, Rome, Italy.
4
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Humanitas Clinical and Research Center, Rozzano, Italy. Electronic address: silvano.sozzani@unibs.it.

Abstract

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.

PMID:
28344062
DOI:
10.1016/j.jid.2017.03.016
[Indexed for MEDLINE]
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