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 Map4k4 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 Map4k4 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细胞活化过程中，淋巴细胞功能相关抗原1（LFA-1）使其配体与抗原呈递细胞（APC）或靶细胞结合，从而增强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T细胞依赖的症状。但是，增强LFA-1功能的治疗潜力的研究较少。在这里，我们表明遗传删除或抑制有丝分裂原激活的蛋白激酶激酶激酶激酶4（MAP4K4）增强了CD8 T细胞上的LFA-1激活，并提高了它们对APC或LFA-1配体的粘附性。另外，丢失Map4k4会增加CD8 T细胞的启动作用，最终导致增强的抗原依赖性激活，增殖，细胞因子产生和细胞毒性活性，导致肿瘤生长受损和对病毒感染的反应得到改善。LFA-1抑制可逆转这些表型。据报道，ERM（ezrin，Radixin和Moesin）蛋白可调节T细胞与APC的结合，但尚未定义T细胞中ERM蛋白的分子调节剂和效应子。在这项研究中，我们证明ERM蛋白充当MAP4K4和LFA-1之间的介体。最后，对许多器官的系统分析显示，成年动物体内可诱导的Map4k4全身缺失是可以接受的。我们的结果发现MAP4K4是增强抗肿瘤和抗病毒免疫力的潜在靶标。