Filamin A Phosphorylation at Serine 2152 by the Serine/Threonine Kinase Ndr2 Controls TCR-Induced LFA-1 Activation in T Cells.

Natalie Waldt,Eric Devroe,Annegret Reinhold,Oliver Stork,Benjamin E Turk,Burkhart Schraven,Yunus Emre Demiray,Christian Freund,Andreas J Müller,Anke Seifert,Stefanie Kliche,Charlie Mix,Peter Reichardt

doi:10.3389/fimmu.2018.02852

Abstract

The integrin LFA-1 (CD11a/CD18) plays a critical role in the interaction of T cells with antigen presenting cells (APCs) to promote lymphocyte differentiation and proliferation. This integrin can be present either in a closed or in an open active conformation and its activation upon T-cell receptor (TCR) stimulation is a critical step to allow interaction with APCs. In this study we demonstrate that the serine/threonine kinase Ndr2 is critically involved in the initiation of TCR-mediated LFA-1 activation (open conformation) in T cells. Ndr2 itself becomes activated upon TCR stimulation and phosphorylates the intracellular integrin binding partner Filamin A (FLNa) at serine 2152. This phosphorylation promotes the dissociation of FLNa from LFA-1, allowing for a subsequent association of Talin and Kindlin-3 which both stabilize the open conformation of LFA-1. Our data suggest that Ndr2 activation is a crucial step to initiate TCR-mediated LFA-1 activation in T cells.

Highlights

T lymphocytes require dynamic regulation of adhesive contacts for their interaction with other cell types
We investigated whether T-cell receptor (TCR) stimulation of Jurkat T cells activates endogenous Ndr2
In this study we report that Ndr2 kinase activity is required for TCR-mediated lymphocyte function-associated antigen-1 (LFA-1) affinity regulation to facilitate T-cell adhesion and interaction with antigen presenting cells (APCs)

Summary

Introduction

T lymphocytes require dynamic regulation of adhesive contacts for their interaction with other cell types. On non-activated T cells, LFA-1 is maintained in a closed conformation with low affinity for its ligand, the Immunoglobulin-like Cell Adhesion Molecule-1 and 2 (ICAM-1/2). Stimulation of the T-cell receptor (TCR) by Ag/MHC-complexes induces a conformational opening of LFA-1 that increases its affinity for ICAM-1 and facilitates avidity modulation (clustering) of LFA-1, a process termed “inside-out signaling” [1,2,3]. Extracellular binding of the ICAM-1 ligands to LFA-1 provides a co-stimulatory signal to the T cells to drive their activation, differentiation and proliferation (“outside-in signaling”) [1, 4]

Methods

Results

Conclusion