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.

中文翻译：

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CD64+炎症2型树突状细胞对自然杀伤细胞的MICa/b依赖性激活有助于自身免疫

原发性干燥综合征 (pSS) 是一种主要由 I 型和 II 型干扰素 (IFN) 介导的炎症性自身免疫性疾病。先天免疫细胞（例如自然杀伤 (NK) 细胞和树突状细胞 (DC)）对 pSS 病理学的潜在贡献仍未得到充分研究。在这里，我们鉴定了与较高细胞毒性功能相关的丰富的 CD16 ⁺ CD56hi NK 细胞亚型，以及表达增加水平的 MICa/b（激活受体 NKG2D 的配体）的炎症性 CD64 ⁺传统树突细胞 (cDC2) 亚型的比例升高，在 pSS 个体中。来自 pSS 患者的循环 cDC2 可有效诱导离体细胞毒性 NK 细胞的激活，并且发现其与 pSS 患者唾液腺 (SG) 中的CD56 ⁺ NK 细胞接近。有趣的是，与 RIG-I/DDX60 通路、IFN I 受体及其靶基因相关的 IFN 特征的转录激活调节 pSS 患者 cDC2 上 NKG2D 配体的表达。最后，注射 Poly I:C 后，SG 体内存在CD64hi RAE-1 ⁺ cDC2 和 NKG2D ⁺ CD11b ⁺ CD27 ^{+ NK 细胞的比例增加。}我们的研究为 NK 和 cDC2 在 pSS 病理学中的贡献和相互作用提供了新的见解，并确定了新的潜在治疗靶点。