Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, Massachusetts, USA.
Harvard Immunology Program, Harvard Medical School, Boston, Massachusetts, USA.
JCI Insight. 2019 Mar 14;5(8):126194. doi: 10.1172/jci.insight.126194.
Regulatory T cells (Tregs) are key modulators of inflammation and are important for the maintenance of peripheral tolerance. Adoptive immunotherapy with polyclonal Tregs holds promise in organ transplantation, graft-versus-host disease, and autoimmune diseases, but may be enhanced by antigen-specific, long-lived Treg cells. We modified primary human Tregs with chimeric antigen-receptors (CARs) bearing different costimulatory domains and performed in vitro analyses of their phenotype and function. While neither the presence of a CAR nor the type of costimulation domain influenced Foxp3 expression in Tregs, the costimulation domain of the CARs affected CAR Treg surface phenotype and functions such as cytokine production. Furthermore, signaling from the CD28 costimulation domain maintained CAR Treg suppressor function, whereas 4-1B costimulation did not. In vivo, CAR Tregs accumulated at sites expressing target antigen, and suppressed antigen specific effector T cell responses; however, only CAR Tregs with CD28 signaling domains were potent inhibitors of effector T cell mediated graft rejection in vivo. Our findings support the use of CD28 based CAR-Tregs for tissue specific immune suppression in the clinic.
调节性 T 细胞（Tregs）是炎症的关键调节剂，对于维持外周耐受非常重要。过继性免疫治疗中使用多克隆 Tregs 有望应用于器官移植、移植物抗宿主病和自身免疫性疾病，但抗原特异性、长寿命的 Treg 细胞可能会增强其疗效。我们使用嵌合抗原受体（CAR）对原代人 Tregs 进行修饰，这些 CAR 带有不同的共刺激结构域，并对其表型和功能进行了体外分析。虽然 CAR 的存在或共刺激结构域的类型都不会影响 Treg 中的 Foxp3 表达，但 CAR 上的共刺激结构域会影响 CAR-Treg 的表面表型和功能，如细胞因子的产生。此外，CD28 共刺激域的信号传导维持了 CAR-Treg 的抑制功能，而 4-1BB 共刺激则没有。在体内，CAR-Tregs 会在表达靶抗原的部位聚集，并抑制抗原特异性效应 T 细胞的反应；然而，只有带有 CD28 信号域的 CAR-Tregs 才能在体内有效抑制效应 T 细胞介导的移植物排斥反应。我们的研究结果支持在临床上使用基于 CD28 的 CAR-Tregs 进行组织特异性免疫抑制。
