Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China; Peking Union Medical College, Chinese Academy of Medical Sciencs, Beijing, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China; Peking Union Medical College, Chinese Academy of Medical Sciencs, Beijing, China; Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China; Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
J Autoimmun. 2023 Sep;139:103087. doi: 10.1016/j.jaut.2023.103087. Epub 2023 Jul 21.
T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is a newly discovered immune checkpoint (IC) that exhibits immunosuppressive function in the regulation of immune system. Activation of TIGIT signaling has emerged as a promising approach for autoimmune disease immunotherapy, such as systemic lupus erythematosus (SLE).
We generated a chimeric protein, TIGIT-immunoglobulin (Ig), by fusing the extracellular domain of murine TIGIT to the Fc region of mouse IgG2a, which was used to investigated the effect of activating the TIGIT signaling in murine lupus models (MRL/lpr and chronic graft-versus-host disease mice). Treated mice were harvested, and samples of serum, kidney, and spleen were collected for outcome evaluation. In vitro treatment of TIGIT-Ig in B cells was used for exploring the roles of TIGIT in toll-like receptor 7 (TLR7)-mediated B cell differentiation and antibody production.
TIGIT-Ig treatment delayed disease progression in both lupus models, accompanied by a decrease in the production of anti-double stranded DNA antibodies (anti-dsDNA), proteinuria, proteinuria/creatinine, and Ig kidney deposition. Additionally, the group treated with TIGIT-Ig displayed a decreased proportion of T helper cell (Th)1 cells, T follicular helper (Tfh) cells, and B-cell subsets, including germinal center B cells (GC B), plasmablasts, and plasma cells, compared to the group treated with control IgG. Interestingly, we also observed an increased proportion of Tregs in the spleen of the TIGIT-Ig group. We have discovered a new way in which activating the TIGIT pathway can regulate B-cell differentiation through the SPI-B-PAX5-XBP1 pathway, resulting in a reduction in autoantibodies.
Together, TIGIT may be a promising IC target for SLE treatment.
T 细胞免疫球蛋白和免疫受体酪氨酸抑制基序（ITIM）结构域（TIGIT）是一种新发现的免疫检查点（IC），在免疫系统调节中具有免疫抑制功能。激活 TIGIT 信号已成为治疗自身免疫性疾病的一种有前途的方法，例如系统性红斑狼疮（SLE）。
我们通过将小鼠 TIGIT 的细胞外结构域与小鼠 IgG2a 的 Fc 区域融合，生成了一种嵌合蛋白 TIGIT-免疫球蛋白（Ig），用于研究激活 TIGIT 信号在小鼠狼疮模型（MRL/lpr 和慢性移植物抗宿主病小鼠）中的作用。采集处理后的小鼠，收集血清、肾脏和脾脏样本进行结果评估。体外 TIGIT-Ig 处理 B 细胞，用于探索 TIGIT 在 Toll 样受体 7（TLR7）介导的 B 细胞分化和抗体产生中的作用。
TIGIT-Ig 治疗延缓了两种狼疮模型的疾病进展，同时减少了抗双链 DNA 抗体（抗 dsDNA）、蛋白尿、蛋白尿/肌酐和 Ig 肾脏沉积的产生。此外，与 IgG 对照组相比，TIGIT-Ig 治疗组的 Th1 细胞、滤泡辅助 T（Tfh）细胞和 B 细胞亚群（包括生发中心 B 细胞（GC B）、浆母细胞和浆细胞）的比例降低，有趣的是，我们还观察到 TIGIT-Ig 组脾脏中 Treg 的比例增加。我们发现了一种新的方式，即通过 SPI-B-PAX5-XBP1 途径激活 TIGIT 途径可以调节 B 细胞分化，从而减少自身抗体。
总之，TIGIT 可能是治疗 SLE 的有希望的 IC 靶点。
