Background/Purpose: Natural Killer (NK) cells are the most abundant innate lymphoid cells, accounting for 10–40% of total lymphocytes in peripheral blood. They adapt to diverse tissue microenvironments and exert tissue-specific functions. Juvenile idiopathic arthritis (JIA) is the most common chronic arthritis of childhood, with oligoarticular/polyarticular (oligo/poly JIA) subtypes comprising about 80% of cases. Although JIA research has primarily focused on T cells, the role of NK cells remains underexplored despite their abundance and potent immunomodulatory functions.

Methods: Peripheral blood, synovial fluid, and synovial tissue biopsies were obtained from children diagnosed with oligoarticular JIA or RF-negative polyarticular JIA, meeting the ACR criteria for JIA. Lymphocytes were isolated using density gradient centrifugation. Cells were analyzed for comprehensive profiling and stimulated to evaluate cytokine production. Synovial tissue biopsy was fixed and assayed for spatial transcriptomics using 10x genomics protocol. Cell types were evaluated for colocalization within the inflamed tissue.

Results: NK cells were classified into two subsets based on CD56 expression: cytotoxic CD56dim and immunomodulatory CD56bright. We discovered that the immunomodulatory CD56bright subset was predominant in JIA synovial fluid, whereas the cytotoxic CD56dim subset made up the majority of peripheral NK cells. These synovial NK cells expressed tissue-residency markers such as CD49a, CD103, and CD69. Functionally, synovial NK cells produced abundant cytokines, including IFN-γ and TNF-α. Although previous reports have identified T cells as the primary producers of GM-CSF in inflammatory arthritis, our data showed that synovial NK cells were one of the main producers of GM-CSF alongside T cells. With GM-CSF being an established stimulant of monocyte differentiation, we analyzed spatial transcriptomic data obtained from synovial tissue biopsy. Here, NK cells were found to be consistently in close proximity with macrophages.

Conclusion: Our data suggests that tissue-resident synovial NK cells may drive monocyte differentiation and macrophage accumulation through elevated GM-CSF secretion, acting as a mechanism to exacerbate inflammation in juvenile arthritis. Our findings reveal novel immunoregulatory functions of synovial NK cells, highlighting their significance in understanding JIA disease pathogenesis and treatment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tissue-resident-natural-killer-cells-may-drive-monocyte-differentiation-and-macrophage-accumulation-in-the-inflamed-joints-of-pediatric-juvenile-idiopathic-arthritis-patients/