학술논문
MICa/b‐dependent activation of natural killer cells by CD64+ inflammatory type 2 dendritic cells contributes to autoimmunity.
Document Type
Article
Author
Sánchez‐Cerrillo, Ildefonso; Calzada‐Fraile, Diego; Triguero‐Martínez, Ana; Calvet‐Mirabent, Marta; Popova, Olga; Delgado‐Arévalo, Cristina; Valdivia‐Mazeyra, Mariel; Ramírez‐Huesca, Marta; de Luis, Enrique Vázquez; Benguría, Alberto; Aceña‐Gonzalo, Teresa; Moreno‐Vellisca, Roberto; de Llano, Magdalena Adrados; de la Fuente, Hortensia; Tsukalov, Ilya; Delgado‐Wicke, Pablo; Fernández‐Ruiz, Elena; Roy‐Vallejo, Emilia; Tejedor‐Lázaro, Reyes; Ramiro, Almudena
Source
Subject
*KILLER cells
*DENDRITIC cells
*INTERFERON receptors
*INTERFERON gamma
*SJOGREN'S syndrome
*AUTOIMMUNITY
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Language
ISSN
0261-4189
Abstract
Primary Sjögren's syndrome (pSS) is an inflammatory autoimmune disorder largely mediated by type I and II interferon (IFN). The potential contribution of innate immune cells, such as natural killer (NK) cells and dendritic cells (DC), to the pSS pathology remains understudied. Here, we identified an enriched CD16+ CD56hi NK cell subset associated with higher cytotoxic function, as well as elevated proportions of inflammatory CD64+ conventional dendritic cell (cDC2) subtype that expresses increased levels of MICa/b, the ligand for the activating receptor NKG2D, in pSS individuals. Circulating cDC2 from pSS patients efficiently induced activation of cytotoxic NK cells ex vivo and were found in proximity to CD56+ NK cells in salivary glands (SG) from pSS patients. Interestingly, transcriptional activation of IFN signatures associated with the RIG‐I/DDX60 pathway, IFN I receptor, and its target genes regulate the expression of NKG2D ligands on cDC2 from pSS patients. Finally, increased proportions of CD64hi RAE‐1+ cDC2 and NKG2D+CD11b+CD27+ NK cells were present in vivo in the SG after poly I:C injection. Our study provides novel insight into the contribution and interplay of NK and cDC2 in pSS pathology and identifies new potential therapy targets. Synopsis: Primary Sjögren´s syndrome (pSS) is an autoimmune disease characterized by inflammation and the development of autoimmunity. Here, we provide phenotypical and functional characteristics of the contribution of innate immune cells, such as natural killer (NK) and dendritic cell (DC) subsets, to pSS pathology. pSS patients show increased proportions of a high cytotoxicity‐associated CD16+ CD56hi NK subset.pSS patients show elevated levels of inflammatory CD64+ dendritic cell subset (cDC2) that expresses increased levels of MICa/b, a ligand for the activating receptor NKG2D.MICa/b expression in cDC2 is upregulated in response to poly I:C stimulation and associated with RIG‐I‐IFN‐INF Receptor signaling.In vivo activation of the RIG‐I/TLR3 pathway leads to recruitment of NK cells and cDC2 to salivary glands and their activation similar to what is seen in pSS patients. [ABSTRACT FROM AUTHOR]