Department of Internal Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, USA.
Sci Immunol. 2022 Oct 14;7(76):eabo0777. doi: 10.1126/sciimmunol.abo0777. Epub 2022 Oct 7.
Both higher- and lower-affinity self-reactive CD4 T cells are expanded in autoimmunity; however, their individual contribution to disease remains unclear. We addressed this question using peptide-MHCII chimeric antigen receptor (pMHCII-CAR) T cells to specifically deplete peptide-reactive T cells in mice. Integration of improvements in CAR engineering with TCR repertoire analysis was critical for interrogating in vivo the role of TCR affinity in autoimmunity. Our original MOG pMHCII-CAR, which targeted only higher-affinity TCRs, could prevent the induction of experimental autoimmune encephalomyelitis (EAE). However, pMHCII-CAR enhancements to pMHCII stability, as well as increased survivability via overexpression of a dominant-negative Fas, were required to target lower-affinity MOG-specific T cells and reverse ongoing clinical EAE. Thus, these data suggest a model in which higher-affinity autoreactive T cells are required to provide the "activation energy" for initiating neuroinflammatory injury, but lower-affinity cells are sufficient to maintain ongoing disease.
在自身免疫中，高亲和性和低亲和性的自身反应性 CD4 T 细胞都被扩增；然而，它们对疾病的个体贡献仍不清楚。我们使用肽-MHCII 嵌合抗原受体 (pMHCII-CAR) T 细胞来专门耗尽小鼠中肽反应性 T 细胞，从而解决了这个问题。CAR 工程的改进与 TCR 库分析的整合对于在体内研究 TCR 亲和力在自身免疫中的作用至关重要。我们最初的靶向仅高亲和性 TCR 的 MOG pMHCII-CAR 可预防实验性自身免疫性脑脊髓炎 (EAE) 的诱导。然而，需要 pMHCII-CAR 增强 pMHCII 的稳定性，以及通过过表达显性负 Fas 提高细胞存活率，以靶向低亲和性 MOG 特异性 T 细胞并逆转正在进行的临床 EAE。因此，这些数据表明了一种模型，即高亲和性自身反应性 T 细胞需要提供“激活能”来引发神经炎症损伤，但低亲和性细胞足以维持持续的疾病。
