Esen et al. showed that CD8+ T cells in mice with inducible KO of the Ser-Thr kinase MAP4K4 have a lower activation threshold, undergo greater early expansion, and mediate enhanced responses in implanted tumor and virus models. In vitro binding of knockdown and overexpressing cells showed MAP4K4 inhibits phosphorylation of moesin (which bridges the cytoskeleton and plasma membrane), LFA-1 activation, and APC-CD8+ T cell conjugate and immune synapse formation. LFA-1 agonism overcomes MAP4K4 inhibition, and TCR engagement reduces MAP4K4 expression. High MAP4K4 expression in cancer patients correlated with poorer survival.
Contributed by Paula Hochman
ABSTRACT: 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.
Author Info: (1) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. (2) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. (3) Department of Mole
Author Info: (1) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. (2) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. (3) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. (4) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. (5) Department of Research Pathology, Genentech, South San Francisco, CA, USA. (6) Department of Translational Immunology, Genentech, South San Francisco, CA, USA. (7) Department of Translational Immunology, Genentech, South San Francisco, CA, USA. (8) Department of Bioinformatics, Genentech, South San Francisco, CA, USA. (9) Department of Translational Oncology, Genentech, South San Francisco, CA, USA. (10) Department of Translational Oncology, Genentech, South San Francisco, CA, USA. (11) Department of Cancer Immunology, Genentech, South San Francisco, CA, USA. (12) Department of Cancer Immunology, Genentech, South San Francisco, CA, USA. (13) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. walsh.kevin@gene.com ye.weilan@gene.com. (14) Department of Molecular Oncology, Genentech, South San Francisco, CA, USA. walsh.kevin@gene.com ye.weilan@gene.com.
