CD8aa+MHC-II+ Cell with Capacity to Terminate Autoimmune Inflammation Is A Novel Antigen-Presenting NK-like cell in Rats

Discovery of immune tolerance mechanisms, which inhibit pre-existing autoimmune inflammation, may provide us with new strategies for treating autoimmune diseases. We have identified a CD8aa+MHC-II+ cell with professional APC capacity during our investigation on spontaneous recovery from autoimmune glomerulonephritis in a rat model. This cell actively invades inflamed target tissue to terminate an on-going autoimmune inflammation by selective killing of effector autoreactive T cells. Now, we showed that this cell used a cytotoxic machinery of Ly49s+ NK cells in killing of target T cells. Thus, this CD8aa+MHC-II+ cell, which previously was thought a professional APC, is an antigen presenting-NK (AP-NK) cell. Following its coupling with target T cells through antigen presentation, killing stimulatory receptor Ly49s6 and co-receptor CD8aa on this cell used non-classic MHC-I RT1CE16 on the target T cells as a ligand to initiate killing. Thus, activated effector T cells with elevated expression of RT1CE16 were highly susceptible to the killing by the CD8aa+ AP-NK cell. Granule cytolytic perforin/granzyme C from this cell subsequently mediated cytotoxicity, and thus, inhibition of granzyme C effectively attenuated the killing. As it can recognize and eliminate effector autoreactive T cells in the inflamed target tissue, CD8aa+ AP-NK cell not only represents a new type of immune cell involved in immune tolerance, but also is a potential candidate for developing a cell-based therapy for pre-existing autoimmune diseases.探索可抑制已存在自身免疫炎症的免疫耐受（immune tolerance）机制，可为自身免疫性疾病的治疗提供全新策略。我们在大鼠模型自身免疫性肾小球肾炎（autoimmune glomerulonephritis）自发恢复的研究中，鉴定出一种具备专职抗原呈递细胞（antigen-presenting cell, APC）功能的CD8αα+MHC-II+细胞。该细胞可主动浸润炎症靶组织，通过选择性杀伤致病性效应自身反应性T细胞，终止正在进展的自身免疫炎症。本研究证实，该细胞借助Ly49s+自然杀伤细胞（natural killer cell, NK）的细胞毒性机制杀伤靶T细胞。因此，这种此前被认为是专职APC的CD8αα+MHC-II+细胞，实为抗原呈递自然杀伤细胞（antigen-presenting-NK, AP-NK）。当其通过抗原呈递与靶T细胞结合后，该细胞表面的杀伤刺激受体Ly49s6与共受体CD8αα，以靶T细胞表面的非经典MHC-I RT1CE16作为配体，启动杀伤程序。因此，RT1CE16表达上调的活化效应T细胞，对CD8αα+ AP-NK细胞的杀伤作用高度易感。该细胞颗粒中的溶细胞成分——穿孔素（perforin）与颗粒酶C（granzyme C）随后介导了细胞毒性效应，因此抑制颗粒酶C可有效削弱其杀伤活性。鉴于该细胞可在炎症靶组织中识别并清除致病性效应自身反应性T细胞，CD8αα+ AP-NK细胞不仅代表了一类参与免疫耐受的新型免疫细胞，同时也是开发针对已存在自身免疫性疾病的细胞治疗方案的潜在候选靶点。