Abstract

Class I phosphoinositide 3-kinases (PI3Ks) constitute a family of enzymes that generates 3-phosphorylated polyphosphoinositides at the cell membrane after stimulation of protein tyrosine (Tyr) kinase-associated receptors or G protein-coupled receptors (GPCRs). The class I PI3Ks are divided into two types: class I(A) p85/p110 heterodimers, which are activated by Tyr kinases, and the class I(B) p110gamma isoform, which is activated by GPCR. Although the T cell receptor (TCR) is a protein Tyr kinase-associated receptor, p110gamma deletion affects TCR-induced T cell stimulation. We examined whether the TCR activates p110gamma, as well as the consequences of interfering with p110gamma expression or function for T cell activation. We found that after TCR ligation, p110gamma interacts with G alpha(q/11), lymphocyte-specific Tyr kinase, and zeta-associated protein. TCR stimulation activates p110gamma, which affects 3-phosphorylated polyphosphoinositide levels at the immunological synapse. We show that TCR-stimulated p110gamma controls RAS-related C3 botulinum substrate 1 activity, F-actin polarization, and the interaction between T cells and antigen-presenting cells, illustrating a crucial role for p110gamma in TCR-induced T cell activation.