Division of Rheumatology and Immunology, Department of Medicine, Duke University School of Medicine, Durham, NC, United States.
Department of Immunology, Duke University School of Medicine, Durham, NC, United States.
Front Immunol. 2021 Mar 22;12:641188. doi: 10.3389/fimmu.2021.641188. eCollection 2021.
Precisely controlled lymphocyte migration is critically required for immune surveillance and successful immune responses. Lymphocyte migration is strictly regulated by chemokines and chemokine receptors. Here we show that protein geranylgeranylation, a form of post-translational protein lipid modification, is required for chemokine receptor-proximal signaling. Mature thymocytes deficient for protein geranylgeranylation are impaired for thymus egress. Circulating mature T cells lacking protein geranylgeranylation fail to home to secondary lymphoid organs or to transmigrate in response to chemokines . Mechanistically, protein geranylgeranylation modifies the γ-subunits of the heterotrimeric small GTPases that are essential for chemokine receptor signaling. In addition, protein geranylgeranylation also promotes the differentiation of IL-17-producing T helper cells while inhibiting the differentiation of Foxp3 regulatory T cells. Finally, mice with T cell lineage-specific deficiency of protein geranylgeranylation are resistant to experimental autoimmune encephalomyelitis induction. This study elucidated a critical role of protein geranylgeranylation in regulating T lymphocyte migration and function.
精确控制淋巴细胞迁移对于免疫监视和成功的免疫反应至关重要。淋巴细胞迁移受到趋化因子和趋化因子受体的严格调节。在这里，我们表明蛋白质香叶基香叶基化，一种翻译后蛋白质脂质修饰形式，是趋化因子受体近端信号所必需的。成熟的胸腺细胞缺乏蛋白质香叶基香叶基化，会影响胸腺输出。循环成熟的 T 细胞缺乏蛋白质香叶基香叶基化，无法归巢到次级淋巴器官，也无法响应趋化因子迁移。从机制上讲，蛋白质香叶基香叶基化修饰了异三聚体小 GTP 酶的 γ 亚基，这些亚基对于趋化因子受体信号至关重要。此外，蛋白质香叶基香叶基化还促进了产生白细胞介素-17 的辅助性 T 细胞的分化，同时抑制了 Foxp3 调节性 T 细胞的分化。最后，T 细胞谱系特异性缺乏蛋白质香叶基香叶基化的小鼠对实验性自身免疫性脑脊髓炎的诱导具有抗性。这项研究阐明了蛋白质香叶基香叶基化在调节 T 淋巴细胞迁移和功能中的关键作用。
