Department of Medicine, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.
Sci Transl Med. 2020 Aug 19;12(557). doi: 10.1126/scitranslmed.aaz3866.
Antigen-specific regulatory T cells (T) engineered with chimeric antigen receptors (CARs) are a potent immunosuppressive cellular therapy in multiple disease models and could overcome shortcomings of polyclonal T therapy. CAR therapy was initially developed with conventional T cells, which have different signaling requirements than do T To date, most of the CAR T studies used second-generation CARs, encoding a CD28 or 4-1BB co-receptor signaling domain and CD3ζ, but it was not known if this CAR design was optimal for T Using a human leukocyte antigen-A2-specific CAR platform and human T, we compared 10 CARs with different co-receptor signaling domains and systematically tested their function and CAR-stimulated gene expression profile. T expressing a CAR encoding CD28wt were markedly superior to all other CARs tested in an in vivo model of graft-versus-host disease. In vitro assays revealed stable expression of Helios and an ability to suppress CD80 expression on dendritic cells as key in vitro predictors of in vivo function. This comprehensive study of CAR signaling domain variants in T can be leveraged to optimize CAR design for use in antigen-specific T therapy.
嵌合抗原受体（CAR）修饰的抗原特异性调节性 T 细胞（T）是一种强大的免疫抑制性细胞疗法，可克服多克隆 T 治疗的缺点。CAR 疗法最初是用传统 T 细胞开发的，其信号要求与 T 不同。迄今为止，大多数 CAR T 研究使用第二代 CAR，编码 CD28 或 4-1BB 共受体信号域和 CD3ζ，但尚不清楚这种 CAR 设计是否最适合 T。我们使用人类白细胞抗原-A2 特异性 CAR 平台和人类 T，比较了 10 种具有不同共受体信号域的 CAR，并系统地测试了它们的功能和 CAR 刺激的基因表达谱。在移植物抗宿主病的体内模型中，表达编码 CD28wt 的 CAR 的 T 明显优于所有其他测试的 CAR。体外试验揭示了 Helios 的稳定表达和抑制树突状细胞上 CD80 表达的能力，这是体外预测体内功能的关键。这项对 T 中 CAR 信号域变体的全面研究可用于优化 CAR 设计，以用于抗原特异性 T 治疗。
