Inositol (1,4,5) trisphosphate 3-kinase B (ItpkB) is central to thymic development by regulating Phosphoinositide 3-kinase (PI3K) downstream of mild and strong TCR signals

T cell development and selection depend on T cell receptor (TCR) signal strength. TCR signaling activates PI3K. PI3K is central to T cell development and selection by regulating T cell survival, proliferation, metabolism, differentiation and migration. PI3K phosphorylates the membrane lipid phosphatidylinositol(4,5)bisphophate (PIP2) into phosphatidylinositol (3,4,5)trisphosphate (PIP3). PIP3 binds PH domains or other domains of proteins and regulates protein function through membrane recruitment. ItpkB catalyzes a very similar reaction as PI3K in the cytosol. It phosphorylates the inositol ring 3- position of the soluble second messenger molecule IP3 to generate soluble inositol(1,3,4,5)tetrakisphosphate (IP4). IP4 can bind to certain PH-domains and alter their ability to bind to PIP3. In this thesis, I will first introduce T cell development and thymic selection. Next, I will describe how multiple receptors cooperate to activate PI3K downstream of the pre-TCR. Then, I will introduce the IP3 3-kinases and discuss how they function in the immune system. I will discuss how IP4 regulates PI3K signaling in thymocyte positive selection. In chapters 2 and 4, I will show how ItpkB controls the kinetics of β-selection, which precedes positive selection. ItpkB loss renders thymocytes hyperresponsive to pre-TCR signaling and metabolically hyperactive. As a consequence, ItpkB-/- thymocyte development becomes costimulation independent and faster than in wild type (wt) mice. In chapter 3, I will show that ItpkB has specific, independent roles in β-selection and positive selection. In chapter 4, I will describe how transgenic ItpkB overexpression in thymocytes unveiled novel ItpkB functions in TCR signaling. In chapter 5, I will show data that suggest that ItpkB has additional functions in processes mediated by strong TCR signals, including thymocyte agonist selection, γδ T cell development and function. By showing that symmetric signaling by PI3K and ItpkB is a broadly relevant signaling paradigm that controls T cell development and function, my research contributes new insights into the molecular mechanisms involved in immunodeficiencies, T cell pathology and signaling by PI3K, an oncogene and key signaling node downstream of many receptors in most cells.