Current rheumatoid arthritis (RA) treatments do not restore immune tolerance. Investigating dendritic cell (DC) populations in human synovial tissue (ST) may reveal pathways to reinstate tolerance in RA. Using single-cell and spatial transcriptomics of ST biopsies, as well as co-culture systems, we identified condition- and niche-specific DC clusters with distinct functions. Healthy tissue contained tolerogenic AXL+ DC2s in the lining niche. In active RA, the hyperplasic lining niche was populated with inflammatory DC3s that activated CCL5-positive effector memory T cells, promoting synovitis. Lymphoid niches that emerged in the sublining layer were enriched with CCR7+ DC2s, which interacted with naive T cells, potentially driving the local expansion of new effector T cells. Remission saw the resolution of these pathogenic niches but lacked recovery of tolerogenic DC2s and exhibited activation of blood precursors of ST-DC3 clusters prior to flare-ups. Targeting pathogenic DC3s or restoring tolerogenic DC2s may help restore immune homeostasis in RA joints.

中文翻译：

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滑膜组织髓系树突状细胞亚群在健康和类风湿性关节炎中表现出不同的组织生态位定位和功能


目前的类风湿性关节炎 （RA） 治疗不能恢复免疫耐受。研究人滑膜组织 （ST） 中的树突状细胞 （DC） 群体可能揭示恢复 RA 耐受性的途径。使用 ST 活检的单细胞和空间转录组学以及共培养系统，我们确定了具有不同功能的条件和生态位特异性 DC 簇。健康组织在衬里生态位中含有耐耐受性的 AXL+ DC2s。在活动性 RA 中，增生内壁生态位中充满了炎性 DC3，这些 DC3 激活 CCL5 阳性效应记忆 T 细胞，促进滑膜炎。出现在亚衬层中的淋巴生态位富含 CCR7+ DC2，CCR7+ DC2 与幼稚 T 细胞相互作用，可能驱动新效应 T 细胞的局部扩增。缓解看到这些致病性生态位的消退，但缺乏致耐受性 DC2 的恢复，并且在发作前表现出 ST-DC3 簇的血液前体激活。靶向致病性 DC3 或恢复耐受性 DC2 可能有助于恢复 RA 关节的免疫稳态。