Regulatory T cells (Tregs) maintain immune tolerance. While Treg-mediated neuroprotective activities are now well-accepted, the lack of defined antigen specificity limits their therapeutic potential. This is notable for neurodegenerative diseases where cell access to injured brain regions is required for disease-specific therapeutic targeting and improved outcomes. To address this need, amyloid-beta (Aβ) antigen specificity was conferred to Treg responses by engineering the T cell receptor (TCR) specific for Aβ (TCRAβ). The TCRAb were developed from disease-specific T cell effector (Teff) clones. The ability of Tregs expressing a transgenic TCRAβ (TCRAβ -Tregs) to reduce Aβ burden, transform effector to regulatory cells, and reverse disease-associated neurotoxicity proved beneficial in an animal model of Alzheimer’s disease. TCRAβ -Tregs were generated by CRISPR-Cas9 knockout of endogenous TCR and consequent incorporation of the transgenic TCRAb identified from Aβ reactive Teff monoclones. Antigen specificity was confirmed by MHC-Aβ-tetramer staining. Adoptive transfer of TCRAβ-Tregs to mice expressing a chimeric mouse-human amyloid precursor protein and a mutant human presenilin-1 followed measured behavior, immune, and immunohistochemical outcomes. TCRAβ-Tregs expressed an Aβ-specific TCR. Adoptive transfer of TCRAβ-Tregs led to sustained immune suppression, reduced microglial reaction, and amyloid loads. 18F-fluorodeoxyglucose radiolabeled TCRAβ-Treg homed to the brain facilitating antigen specificity. Reduction in amyloid load was associated with improved cognitive functions. TCRAβ-Tregs reduced amyloid burden, restored brain homeostasis, and improved learning and memory, supporting the increased therapeutic benefit of antigen specific Treg immunotherapy for AD.

中文翻译：

---

β淀粉样蛋白特异性调节T细胞减轻APP/PS1小鼠阿尔茨海默氏病病理学

调节性 T 细胞 (Treg) 维持免疫耐受。虽然 Treg 介导的神经保护活性现已被广泛接受，但缺乏明确的抗原特异性限制了其治疗潜力。这对于神经退行性疾病来说是值得注意的，在神经退行性疾病中，需要细胞进入受损的大脑区域来实现疾病特异性治疗目标和改善结果。为了满足这一需求，通过设计对 Aβ (TCRAβ) 具有特异性的 T 细胞受体 (TCR)，将淀粉样蛋白 -β (Aβ) 抗原特异性赋予 Treg 反应。 TCRAb 是从疾病特异性 T 细胞效应 (Teff) 克隆开发而来。表达转基因 TCRAβ (TCRAβ-Tregs) 的 Tregs 能够减少 Aβ 负荷、将效应细胞转化为调节细胞以及逆转疾病相关的神经毒性，这在阿尔茨海默病动物模型中被证明是有益的。 TCRAβ-Tregs 是通过 CRISPR-Cas9 敲除内源性 TCR 并随后掺入从 Aβ 反应性 Teff 单克隆中鉴定出的转基因 TCRAb 产生的。通过MHC-Aβ-四聚体染色证实抗原特异性。将 TCRAβ-Treg 过继转移至表达嵌合的小鼠-人淀粉样前体蛋白和突变的人早老素-1 的小鼠中，随后测量行为、免疫和免疫组织化学结果。 TCRAβ-Tregs 表达 Aβ 特异性 TCR。 TCRAβ-Treg 的过继转移导致持续的免疫抑制、小胶质细胞反应和淀粉样蛋白负荷的减少。 18F-氟脱氧葡萄糖放射性标记的 TCRAβ-Treg 归巢至大脑，促进抗原特异性。淀粉样蛋白负荷的减少与认知功能的改善相关。 TCRAβ-Treg 减少了淀粉样蛋白负担，恢复了大脑稳态，并改善了学习和记忆，支持抗原特异性 Treg 免疫疗法对 AD 的治疗效果的增加。