Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Center for Data Sciences, Brigham and Women's Hospital, Boston, MA 02115, USA.
Sci Transl Med. 2022 Jun 15;14(649):eabo0686. doi: 10.1126/scitranslmed.abo0686.
T cell-derived pro-inflammatory cytokines are a major driver of rheumatoid arthritis (RA) pathogenesis. Although these cytokines have traditionally been attributed to CD4 T cells, we have found that CD8 T cells are notably abundant in synovium and make more interferon (IFN)-γ and nearly as much tumor necrosis factor (TNF) as their CD4 T cell counterparts. Furthermore, using unbiased high-dimensional single-cell RNA-seq and flow cytometric data, we found that the vast majority of synovial tissue and synovial fluid CD8 T cells belong to an effector CD8 T cell population characterized by high expression of granzyme K (GzmK) and low expression of granzyme B (GzmB) and perforin. Functional experiments demonstrate that these GzmK GzmB CD8 T cells are major cytokine producers with low cytotoxic potential. Using T cell receptor repertoire data, we found that CD8 GzmK GzmB T cells are clonally expanded in synovial tissues and maintain their granzyme expression and overall cell state in blood, suggesting that they are enriched in tissue but also circulate. Using GzmK and GzmB signatures, we found that GzmK-expressing CD8 T cells were also the major CD8 T cell population in the gut, kidney, and coronavirus disease 2019 (COVID-19) bronchoalveolar lavage fluid, suggesting that they form a core population of tissue-associated T cells across diseases and human tissues. We term this population tissue-enriched expressing GzmK or T CD8 cells. Armed to produce cytokines in response to both antigen-dependent and antigen-independent stimuli, CD8 T cells have the potential to drive inflammation.
T 细胞衍生的促炎细胞因子是类风湿关节炎 (RA) 发病机制的主要驱动因素。尽管这些细胞因子传统上归因于 CD4 T 细胞，但我们发现 CD8 T 细胞在滑膜中明显丰富，并且产生的干扰素 (IFN)-γ 几乎与 CD4 T 细胞相当，产生的肿瘤坏死因子 (TNF) 也几乎与其相当。此外，使用无偏的高维单细胞 RNA-seq 和流式细胞术数据，我们发现绝大多数滑膜组织和滑膜液 CD8 T 细胞属于效应 CD8 T 细胞群体，其特征是高水平表达颗粒酶 K (GzmK) 和低水平表达颗粒酶 B (GzmB) 和穿孔素。功能实验表明，这些 GzmK GzmB CD8 T 细胞是主要的细胞因子产生者，细胞毒性潜力低。使用 T 细胞受体库数据，我们发现 CD8 GzmK GzmB T 细胞在滑膜组织中克隆扩增，并在血液中保持其颗粒酶表达和整体细胞状态，表明它们在组织中丰富，但也循环。使用 GzmK 和 GzmB 特征，我们发现 GzmK 表达的 CD8 T 细胞也是肠道、肾脏和 2019 年冠状病毒病 (COVID-19) 支气管肺泡灌洗液中的主要 CD8 T 细胞群体，表明它们形成了一个核心群体组织相关 T 细胞在疾病和人类组织中。我们将这群细胞称为组织富集表达 GzmK 或 T 细胞的 CD8 细胞。武装以响应抗原依赖性和抗原非依赖性刺激产生细胞因子，CD8 T 细胞有可能引发炎症。
