Department of Biotechnology, Yonsei University College of Life Science and Biotechnology, Seoul, Republic of Korea.
Molecular Neurobiology Laboratory, Department of Psychiatry and McLean Hospital, Harvard Medical School, Belmont, MA, USA.
Immunol Med. 2022 Jun;45(2):119-127. doi: 10.1080/25785826.2022.2031812. Epub 2022 Feb 7.
Th17 cells are implicated in the pathogenesis of several autoimmune diseases. During the inflammation, Th17 cells exposed to IL-12 can shift towards the Th1 phenotype. These shifted cells are defined as 'non-classic Th1 cells'. Th17-derived non-classic Th1 cells play a critical role in late-onset chronic inflammatory diseases and are more pathogenic than the unshifted Th17 cells. Eomes is a transcription factor highly expressed in non-classic Th1 cells. To study the functional role of Eomes without genetic alteration, novel recombinant protein, ntEomes-TMD, was generated by fusing TMD of Eomes and Hph-1-PTD that facilitate intracellular delivery of its cargo molecule. ntEomes-TMD was delivered into the nucleus of the cells without influencing the T cell activation and cytotoxicity. ntEomes-TMD specifically inhibited the Eomes- and ROR-γt-mediated transcription and suppressed the Th1 and Th17 differentiation. Interestingly, ntEomes-TMD blocked the generation of non-classic Th1 cells from Th17 cells, leading to the inhibition of IFN-γ and GM-CSF secretion. In EAE, ntEomes-TMD alleviated the symptoms of EAE, and the combination treatment using ntEomes-TMD and anti-IL-17 mAb together showed better therapeutic efficacy than anti-IL-17 mAb treatment. The results suggest that ntEomes-TMD can be a new therapeutic reagent for treating chronic inflammatory diseases associated with non-classic Th1 cells.
Th17 细胞参与多种自身免疫性疾病的发病机制。在炎症过程中，暴露于 IL-12 的 Th17 细胞可向 Th1 表型转变。这些转变后的细胞被定义为“非经典 Th1 细胞”。Th17 衍生的非经典 Th1 细胞在迟发性慢性炎症性疾病中发挥关键作用，比未转变的 Th17 细胞更具致病性。Eomes 是一种在非经典 Th1 细胞中高度表达的转录因子。为了在不改变基因的情况下研究 Eomes 的功能作用，通过融合 Eomes 的 TMD 和 Hph-1-PTD 生成了新型重组蛋白 ntEomes-TMD，这有利于其货物分子的细胞内递送。ntEomes-TMD 被递送到细胞的细胞核中，而不影响 T 细胞的激活和细胞毒性。ntEomes-TMD 特异性抑制 Eomes 和 ROR-γt 介导的转录，并抑制 Th1 和 Th17 分化。有趣的是，ntEomes-TMD 阻止了 Th17 细胞向非经典 Th1 细胞的生成，导致 IFN-γ 和 GM-CSF 分泌受到抑制。在 EAE 中，ntEomes-TMD 缓解了 EAE 的症状，并且使用 ntEomes-TMD 和抗 IL-17 mAb 的联合治疗比抗 IL-17 mAb 治疗显示出更好的治疗效果。结果表明，ntEomes-TMD 可以成为治疗与非经典 Th1 细胞相关的慢性炎症性疾病的新治疗试剂。
