Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
Cell Rep Med. 2020 Apr 21;1(1). doi: 10.1016/j.xcrm.2020.100003. Epub 2020 Mar 25.
Follicular helper T cells (T) are critical for vaccine and infection elicitation of long-lived humoral immunity, but exaggerated T responses can promote autoimmunity and other pathologies. It is unfortunate that no clinical interventions exist for the selective depletion of follicular T cells to alleviate these diseases. We engineered a chimeric antigen receptor (CAR) facilitating the specific targeting of cells with high expression levels of human programmed cell death protein 1 (PD-1), a cardinal feature of follicular T cells. CAR-expressing human natural killer (NK) cells robustly and discriminately eliminated PD-1 follicular human T cells and in a humanized mouse model of lupus-like disease while sparing B cells and other PD-1 T cell subsets, including regulatory T cells. These results establish a strategy for specific targeting of PD-1 T cells that can be advanced as a clinical tool for the selective depletion of pathogenic follicular T cells or other PD-1 target cells in certain disease states.
滤泡辅助 T 细胞（T 细胞）对于疫苗和感染引发的长效体液免疫至关重要，但过度的 T 细胞反应会促进自身免疫和其他病理状况。不幸的是，目前尚无临床干预措施可用于选择性耗尽滤泡 T 细胞以缓解这些疾病。我们设计了一种嵌合抗原受体（CAR），能够特异性靶向高表达人类程序性细胞死亡蛋白 1（PD-1）的细胞，这是滤泡 T 细胞的一个主要特征。表达 CAR 的人自然杀伤（NK）细胞能够强有力且有区别地消除 PD-1 滤泡性人 T 细胞，并且在狼疮样疾病的人源化小鼠模型中能够特异性消除 PD-1 滤泡性人 T 细胞，同时还能保留 B 细胞和其他 PD-1 T 细胞亚群，包括调节性 T 细胞。这些结果确立了一种针对 PD-1 T 细胞的特异性靶向策略，可作为一种临床工具，用于在某些疾病状态下选择性耗尽致病性滤泡 T 细胞或其他 PD-1 靶细胞。
