Date: Monday, November 14, 2022
Session Title: Innate Immunity Poster: Basic and Translational Science
Session Type: Poster Session D
Session Time: 1:00PM-3:00PM
Background/Purpose: Altered Th17, CD8+ T cell and B cell adaptative immune responses in patients with primary Sjögren syndrome (pSS) have been characterized in salivary glands (SG). However, although innate cells such as natural killer (NK) and dendritic cells (DC) have been observed in the SG. However, their potential cellular and molecular mechanism involved in activation of NK cells in pSS have been less investigates. We identify a dendritic cell subset with phenotypic and functional characteristics capable to boost NK cells and defined pathogenic crosstalk between NK cells and adaptative Th17 CD4+ T cells.
Methods: PBMCs from 40 pSS patients and 42 healthy donors (HD) were used for phenotypical analysis of myeloid and NK cell subsets by flow cytometry. Sorted Mo, CD1c+ and CD141+ cDC from each cohort were used to RNA-seq analysis and co-culture with sorted NK cells for test functional interactions. Regulation of ligands for NK cell receptors on cDC was analyzed after stimulation with poly I:C using specific siRNAs. Finally, DC and NK cell phenotypes and interactions with adaptative immune cells were analyzed using an experimental SS model induced by injections of poly I:C in combination with an NK cell-depleting antibody.
Results: We identified enriched proportions of transitional CD16+ CD56hi NK cells in pSS patients characterized by increased levels of NKG2D (p< 0,0001), IFNg and TNFa (p=0.01) and increased cytotoxic activity in pSS individuals compared to HD. In addition, we detected significantly basal higher expression (p=0.001) of Slamf7 and MICab (p< 0.0001) on circulating CD1c+ cDC exhibiting transcriptional signatures involving the RIG-I/DDX60 RNA sensors and their target genes. This phenotype was associated with higher functional ability of CD1c+ cDC to activate cytotoxic NK cells ex vivo compared to other myeloid subsets. Importantly, expression of MICab was more efficiently induced on cDCs from pSS than cDCs from HD after stimulation with poly I:C and was dependent on expression of RIG-I, DDX60 intracellular RNA sensors. Importantly, more mature cytotoxic NK cells exhibiting upregulated NKG2D and CD64hi CD1c+ cDC expressing higher levels of RAE-I were detected specifically in the SG in a murine SS model. Finally, NK cell depletion was associated with reduced levels of IL-17 in CD4+ T cells, IFNg+ CD107a+ CD8+ T cells and proportions of B220+ B cells in the SG from this murine SS model.
Conclusion: Thus, our study provides new evidence supporting a role of NK cells during pSS pathology and adds novel mechanisms in the crosstalk between innate and adaptative immune system that could contribute to pSS pathology and be used as target for future therapies.
To cite this abstract in AMA style:Sánchez Cerrillo I, Calvet Mirabent M, Triguero A, Calzada Fraile D, Valdivia M, Ramírez M, Vázquez de Luis E, Benguría Filippini A, Moreno R, Adrados de llano M, de la Fuente H, Tsukalov I, Roy Vallejo E, Ramiro A, Iborra S, Sánchez Madrid F, Dopazo A, Gonzalez I, Castañeda S, Martín Gayo E. Potential Regulation of NK Cells by CD1c+ Dendritic Cells Through RIG-I/DDX60 Pathway Involved in Th17 Responses in Primary Sjögren Syndrome [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/potential-regulation-of-nk-cells-by-cd1c-dendritic-cells-through-rig-i-ddx60-pathway-involved-in-th17-responses-in-primary-sjogren-syndrome/. Accessed May 27, 2023.
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