Understanding the mechanisms that regulate T cell immunity is critical for the development of effective therapies for diseases associated with T cell dysfunction, including autoimmune diseases, chronic infections, and cancer. Co-inhibitory “checkpoint molecules,” such as programmed cell death protein-1, balance excessive or prolonged immune activation by T cell–intrinsic signaling. Here, by screening for mediators of natural killer (NK) cell recognition on T cells, we identified the immunoglobulin superfamily ligand B7H6 to be highly expressed by activated T cells, including patient-infused CD19-targeting chimeric antigen receptor (CAR) T cells. Unlike other checkpoint molecules, B7H6 mediated NKp30-dependent recognition and subsequent cytolysis of activated T cells by NK cells. B7H6 + T cells were prevalent in the tissue and blood of several diseases, and their abundance in tumor tissue positively correlated with clinical response in a cohort of patients with immune checkpoint inhibitor–treated esophageal cancer. In humanized mouse models, NK cell surveillance via B7H6 limited the persistence and antitumor activity of CAR T cells, and its genetic deletion enhanced T cell proliferation and persistence. Together, we provide evidence of B7H6 protein expression by activated T cells and suggest the B7H6-NKp30 axis as a therapeutically actionable NK cell–dependent immune checkpoint that regulates human T cell function.

中文翻译：

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免疫球蛋白超家族配体 B7H6 使 T 细胞对 NK 细胞监视做出反应

了解调节 T 细胞免疫的机制对于开发与 T 细胞功能障碍相关的疾病（包括自身免疫性疾病、慢性感染和癌症）的有效疗法至关重要。共抑制性“检查点分子”，例如程序性细胞死亡蛋白-1，通过 T 细胞内在信号传导来平衡过度或长时间的免疫激活。在这里，通过筛选 T 细胞上自然杀伤 (NK) 细胞识别的介质，我们鉴定了活化的 T 细胞（包括患者输注的靶向 CD19 的嵌合抗原受体 (CAR) T 细胞）高度表达的免疫球蛋白超家族配体 B7H6。与其他检查点分子不同，B7H6 介导 NKp30 依赖性识别以及随后 NK 细胞对活化 T 细胞的细胞溶解。 B7H6+T 细胞在多种疾病的组织和血液中普遍存在，它们在肿瘤组织中的丰度与免疫检查点抑制剂治疗的食管癌患者队列的临床反应呈正相关。在人源化小鼠模型中，通过 B7H6 进行的 NK 细胞监视限制了 CAR T 细胞的持久性和抗肿瘤活性，其基因缺失增强了 T 细胞的增殖和持久性。我们共同提供了活化 T 细胞表达 B7H6 蛋白的证据，并建议 B7H6-NKp30 轴作为治疗上可操作的 NK 细胞依赖性免疫检查点，调节人类 T 细胞功能。