Research ArticleT CELLS

MAP4K4 negatively regulates CD8 T cell–mediated antitumor and antiviral immunity

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Science Immunology  27 Mar 2020:
Vol. 5, Issue 45, eaay2245
DOI: 10.1126/sciimmunol.aay2245

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Activation enhancer

CD8+ T cell activation is dependent on encounters with antigen-presenting cells (APCs) through immune synapse formation, which involves binding interactions mediated by multiple molecules on T cells, including lymphocyte function-associated antigen–1 (LFA-1). Here, Esen et al. show that mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) suppresses LFA-1 activation. CD8+ T cell activation is increased upon genetic deletion of Map4k4, which is caused by reduced phosphorylation of ERM (ezrin, radixin, and moesin) proteins that leads to enhanced LFA-1 activation, greater T cell–APC conjugation, and increased CD8+ T cell functionality. Together, these findings define MAP4K4 as a negative regulator of CD8 T cell activation.


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.

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