Annular PIP₃accumulation controls actin architecture and modulates cytotoxicity at the immunological synapse

Abstract

The immunological synapse formed by a T lymphocyte on the surface of a target cell contains a peripheral ring of filamentous actin (F-actin) that promotes adhesion and facilitates the directional secretion of cytokines and cytolytic factors. We show that growth and maintenance of this F-actin ring is dictated by the annular accumulation of phosphatidylinositol trisphosphate (PIP 3 ) in the synaptic membrane. PIP 3 functions in this context by recruiting the exchange factor Dock2 to the periphery of the synapse, where it drives actin polymerization through the Rho-family GTPase Rac. We also show that synaptic PIP 3 is generated by class IA phosphoinositide 3-kinases that associate with T cell receptor microclusters and are activated by the GTPase Ras. Perturbations that inhibit or promote PIP 3 -dependent F-actin remodeling dramatically affect T cell cytotoxicity, demonstrating the functional importance of this pathway. These results reveal how T cells use lipid-based signaling to control synaptic architecture and modulate effector responses.

Phosphatases of regenerating liver balance F-actin rearrangements during T cell activation through WD repeat containing protein 1

“…Interestingly, WDR1 has been proposed to regulate constitutive secretion in non-lymphoid cells (Lopez-Coral et al, 2018) and in our model PRLs might regulate secretion via WDR1. Nonetheless PRL-3 has been proposed to dephosphorylate phosphoinositide PI(4,5)P2 (McParland et al, 2011), which might support adequate PIP3 local levels for F-actin accumulation at the IS (Le Floc'h et al, 2013). A mechanism mediated by PIs might be also accounting for the observed F-actin, IL-2 or LFA-1 phenotype found here in PRL-1 or PRL-2 depleted cells.…”