3rd Focused Meeting on PI3K Signalling and Disease Biochemical Society Focused Meeting 3rd Focused Meeting on PI3K Signalling and Disease Biochemical Society Focused Meeting held at Bath Assembly Rooms, U.K., 6–8 November 2006. Organized and Edited by B. Hemmings (Friedrich Miescher Institute for Biomedical Research, Switzerland), B. Vanhaesebroeck (Ludwig Institute for Cancer Research, U.K.), S. Ward (Bath, U.K.) and M. Welham (Bath, U.K.). The PI3K p110δ controls T-cell development, differentiation and regulation D.T. Patton, F. Garc ¸on and K. Okkenhaug 1 Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB2 4AT, U.K. Abstract PI3Ks (phosphoinositide 3-kinases) regulate diverse cellular functions such as metabolism, growth, gene expression and migration. The p110δ isoform of PI3K is mainly expressed in cells of the immune system and contributes to cellular and humoral immunity. In the thymus, p110δ and p110γ play complementary roles in regulating the transition through key developmental checkpoints. In addition, p110δ regulates the differentiation of peripheral Th (helper T-cells) towards the Th1 and Th2 lineages. Moreover, p110δ is critical for Treg (regulatory T-cell) function. Here, we review the role of PI3Ks in T-cell development and function. Introduction The TCR (T-cell receptor) triggers sequential activation of the tyrosine kinases Lck and ZAP-70 [ζ -chain (TCR)-associated protein kinase of 70 kDa], which together nucleate and activate a signalling complex composed of the transmembrane adaptor LAT (linker for activation of T-cells), Vav, SLP-76 [SH2 (Src homology 2) domain-containing leucocyte protein of 76 kDa], PLCγ (phospholipase Cγ ), PI3K (phosphoino- sitide 3-kinase) and other signalling proteins [1,2]. PLCγ hydrolyses PtdIns(4,5)P 2 to release Ins(1,4,5)P 3 into the cyto- sol, leaving DAG (diacylglycerol) at the plasma membrane. Increased Ins(1,4,5)P 3 levels lead to a biphasic elevation in the cytosolic calcium concentrations and nuclear translocation of NFAT (nuclear factor of activated T-cells) transcription factors which bind to the promoters of most cytokine genes [3]. DAG activates RasGRP [Ras GRP (guanine nucleotide- Key words: colitis, forkhead box O (Foxo), p110δ, phosphoinositide 3-kinase (PI3K), T-cell, thymocyte. Abbreviations used: APC, antigen presenting cell; DAG, diacylglycerol; DN, double negative; DP, double positive; ERK, extracellular-signal-regulated kinase; Foxo, forkhead box O; GPCR, G- protein-coupled receptor; IL-4, interleukin 4; NF-κB, nuclear factor κB; PH domain, pleckstrin homology domain; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B; PLCγ , phospholipase Cγ ; PTEN, phosphatase and tensin homologue deleted on chromosome 10; RAG, recombination- activating gene; SH2, Src homology 2; SP, single positive; TCR, T-cell receptor; Treg, regulatory T-cell; WT, wild-type. 1 To whom correspondence should be addressed (email klaus.okkenhaug@bbsrc.ac.uk). releasing protein)], which stimulates the exchange of GDP for GTP on Ras and the consequent activation of the ERK (extracellular-signal-regulated kinase) signalling cascade, which leads to the activation of Fos and other transcrip- tion factors. DAG also activates PKCθ (protein kinase Cθ ), which activates the NF-κ B (nuclear factor κ B) signalling pathway via a complex of proteins that regulate Iκ B (inhib- itory κ B) kinase activity [4]. PKD (protein kinase D), whose role has yet to be fully defined, but which may be important for chromatin remodelling, is also regulated by DAG [5,6]. Thus PLCγ activation on its own is sufficient to initiate signalling pathways leading to proliferation and transcrip- tional activation. PI3Ks (phosphoinositide 3-kinases) phosphorylate PtdIns(4,5)P 2 to produce PtdIns(3,4,5)P 3 at the plasma mem- brane. Class IA PI3Ks are recruited to the TCR signalling by a mechanism that has yet to be defined; however, their activation is among the earliest detectable upon T-cell activ- ation [7–10]. Class IA PI3Ks are composed of one of five regulatory subunits (p85α, p55α, p50α, p85β or p55γ ) attached to one of three catalytic subunits (p110α, p110β or p110δ) [11,12]. Each regulatory subunit is able to bind to any of the catalytic subunits with equal probability. PI3K signalling is antagonized by the 3-inositol phosphatase PTEN (phosphatase and tensin homologue deleted on C  2007 Biochemical Society 167