Department of Molecular Oncology, Genentech, South San Francisco, CA, USA.
Department of Research Pathology, Genentech, South San Francisco, CA, USA.
Sci Immunol. 2020 Mar 27;5(45). doi: 10.1126/sciimmunol.aay2245.
During cytotoxic T cell activation, lymphocyte function-associated antigen-1 (LFA-1) engages its ligands on antigen-presenting cells (APCs) or target cells to enhance T cell priming or lytic activity. Inhibiting LFA-1 dampens T cell-dependent symptoms in inflammation, autoimmune diseases, and graft-versus-host disease. However, the therapeutic potential of augmenting LFA-1 function is less explored. Here, we show that genetic deletion or inhibition of mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) enhances LFA-1 activation on CD8 T cells and improves their adherence to APCs or LFA-1 ligand. In addition, loss of increases CD8 T cell priming, which culminates in enhanced antigen-dependent activation, proliferation, cytokine production, and cytotoxic activity, resulting in impaired tumor growth and improved response to viral infection. LFA-1 inhibition reverses these phenotypes. The ERM (ezrin, radixin, and moesin) proteins reportedly regulate T cell-APC conjugation, but the molecular regulator and effector of ERM proteins in T cells have not been defined. In this study, we demonstrate that the ERM proteins serve as mediators between MAP4K4 and LFA-1. Last, systematic analyses of many organs revealed that inducible whole-body deletion of in adult animals is tolerated under homeostatic conditions. Our results uncover MAP4K4 as a potential target to augment antitumor and antiviral immunity.
在细胞毒性 T 细胞激活过程中，淋巴细胞功能相关抗原-1（LFA-1）与其在抗原呈递细胞（APC）或靶细胞上的配体结合，以增强 T 细胞的启动或裂解活性。抑制 LFA-1 可减轻炎症、自身免疫性疾病和移植物抗宿主病中的 T 细胞依赖性症状。然而，增强 LFA-1 功能的治疗潜力尚未得到充分探索。在这里，我们表明，丝裂原活化蛋白激酶激酶激酶激酶 4（MAP4K4）的基因缺失或抑制增强了 CD8 T 细胞上的 LFA-1 活化，并改善了它们与 APC 或 LFA-1 配体的黏附。此外，缺失 增加了 CD8 T 细胞的启动，最终导致抗原依赖性激活、增殖、细胞因子产生和细胞毒性活性增强，从而导致肿瘤生长受损和对病毒感染的反应改善。LFA-1 抑制逆转了这些表型。ERM（ezrin、radixin 和 moesin）蛋白据报道可调节 T 细胞与 APC 的连接，但 T 细胞中 ERM 蛋白的分子调节剂和效应物尚未确定。在这项研究中，我们证明了 ERM 蛋白是 MAP4K4 和 LFA-1 之间的中介物。最后，对许多器官的系统分析表明，在稳态条件下，成年动物中诱导性全身性缺失 是可以耐受的。我们的研究结果揭示了 MAP4K4 作为增强抗肿瘤和抗病毒免疫的潜在靶点。
