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Phosphoinositide 3–kinase participates in T cell receptor–induced T cell activation

¹ Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB)/Consejo Superior de Investigaciones Cientificas, Madrid 28049, Spain
² Department of Genetics Biology and Biochemistry, Center for Molecular Biotechnology, University of Torino, 10126 Turin, Italy
³ Department of Clinical and Biological Sciences, Institute of Biochemistry and Genetics, University of Basel, 4058 Basel, Switzerland

CORRESPONDENCE Domingo F. Barber: dfbarber{at}cnb.uam.es

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 p110 isoform, which is activated by GPCR. Although the T cell receptor (TCR) is a protein Tyr kinase–associated receptor, p110 deletion affects TCR-induced T cell stimulation. We examined whether the TCR activates p110, as well as the consequences of interfering with p110 expression or function for T cell activation. We found that after TCR ligation, p110 interacts with G_q/11, lymphocyte-specific Tyr kinase, and -associated protein. TCR stimulation activates p110, which affects 3-phosphorylated polyphosphoinositide levels at the immunological synapse. We show that TCR-stimulated p110 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 p110 in TCR-induced T cell activation.

Abbreviations used: CXCR, CXC chemokine receptor; GPCR, G protein–coupled receptor; IS, immunological synapse; ITAM, immunoreceptor Tyr-based activation motif; Lck, lymphocyte-specific Tyr kinase; MAPK, mitogen-activated protein kinase; PCC, pigeon cytochrome c; PH, pleckstrin homology; PI3K, phosphoinositide 3–kinase; PIP₂, phosphatidylinositol-3, 4-biphosphate; PIP₃, phosphatidylinositol-3,4,5-trisphosphate; PKB, protein kinase B; Rac1, RAS-related C3 botulinum substrate 1; SEE, staphylococcal enterotoxin E; SH2, Src homology 2; Tg, transgenic; TRIM, TCR-interacting molecule; Tyr, tyrosine; ZAP70, -associated protein.

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