Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney-Kimmel Comprehensive Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
Immunohorizons. 2023 Jun 1;7(6):493-507. doi: 10.4049/immunohorizons.2300016.
In order to study mechanistic/mammalian target of rapamycin's role in T cell differentiation, we generated mice in which Rheb is selectively deleted in T cells (T-Rheb-/- C57BL/6J background). During these studies, we noted that T-Rheb-/- mice were consistently heavier but had improved glucose tolerance and insulin sensitivity as well as a marked increase in beige fat. Microarray analysis of Rheb-/- T cells revealed a marked increase in expression of kallikrein 1-related peptidase b22 (Klk1b22). Overexpression of KLK1b22 in vitro enhanced insulin receptor signaling, and systemic overexpression of KLK1b22 in C57BL/6J mice also enhances glucose tolerance. Although KLK1B22 expression was markedly elevated in the T-Rheb-/- T cells, we never observed any expression in wild-type T cells. Interestingly, in querying the mouse Immunologic Genome Project, we found that Klk1b22 expression was also increased in wild-type 129S1/SVLMJ and C3HEJ mice. Indeed, both strains of mice demonstrate exceptionally improved glucose tolerance. This prompted us to employ CRISPR-mediated knockout of KLK1b22 in 129S1/SVLMJ mice, which in fact led to reduced glucose tolerance. Overall, our studies reveal (to our knowledge) a novel role for KLK1b22 in regulating systemic metabolism and demonstrate the ability of T cell-derived KLK1b22 to regulate systemic metabolism. Notably, however, further studies have revealed that this is a serendipitous finding unrelated to Rheb.
为了研究机械/哺乳动物雷帕霉素靶蛋白（mTOR）在 T 细胞分化中的作用，我们生成了 T 细胞中 Rheb 选择性缺失的小鼠（Rheb-/- C57BL/6J 背景）。在这些研究中，我们注意到 Rheb-/- 小鼠的体重一直较重，但葡萄糖耐量和胰岛素敏感性得到改善，米色脂肪明显增加。Rheb-/- T 细胞的基因芯片分析显示激肽释放酶 1 相关肽酶 b22（Klk1b22）的表达明显增加。KLK1b22 的体外过表达增强了胰岛素受体信号，并且 C57BL/6J 小鼠中 KLK1b22 的全身过表达也增强了葡萄糖耐量。尽管 Rheb-/- T 细胞中的 KLK1B22 表达明显升高，但在野生型 T 细胞中从未观察到任何表达。有趣的是，在查询小鼠免疫基因组计划时，我们发现 Klk1b22 在野生型 129S1/SVLMJ 和 C3HEJ 小鼠中的表达也增加了。事实上，这两种品系的小鼠都表现出异常改善的葡萄糖耐量。这促使我们在 129S1/SVLMJ 小鼠中使用 CRISPR 介导的 KLK1b22 敲除，实际上导致葡萄糖耐量降低。总的来说，我们的研究揭示（据我们所知）KLK1b22 在调节全身代谢中的新作用，并证明了 T 细胞衍生的 KLK1b22 调节全身代谢的能力。值得注意的是，然而，进一步的研究表明，这是一个与 Rheb 无关的偶然发现。
