Abstract
Virtually all aspects of T and B lymphocyte development, homeostasis, activation, and effector function are impacted by the interaction of their clonally distributed antigen receptors with antigens encountered in their respective environments. Antigen receptors mediate their effects by modulating intracellular signaling pathways that ultimately impinge on the cytoskeleton, bioenergetic pathways, transcription, and translation. Although these signaling pathways are rather well described at this point, especially those steps that are most receptor-proximal, how such pathways contribute to more quantitative aspects of lymphocyte function is still being elucidated. One of the signaling pathways that appears to be involved in this “tuning” process is controlled by the lipid kinase PI3K. Here we review recent key findings regarding both the triggering/enhancement of PI3K signals (via BCAP and ICOS) as well as their regulation (via PIK3IP1 and PHLPP) and how these signals integrate and determine cellular processes. Lymphocytes display tremendous functional plasticity, adjusting their metabolism and gene expression programs to specific conditions depending on their tissue of residence and the nature of the infectious threat to which they are responding. We give an overview of recent findings that have contributed to this model, with a focus on T cells, including what has been learned from patients with gain-of-function mutations in PI3K as well as lessons from cancer immunotherapy approaches.
Highlights
All aspects of T and B lymphocyte development, homeostasis, activation, and effector function are impacted by the interaction of their clonally distributed antigen receptors with antigens encountered in their respective environments
These cellular cues, whether they are sensed through receptors for antigen (T cell receptor for antigen [TCR]), membrane immunoglobulin, cytokines, or other growth factors, are integrated in lymphocytes by signaling pathways that sustain and/or trigger the differentiation of these cells
Activated PLC-γ mediates the production of the critical second messengers diacylglycerol (DAG) and inositol tris-phosphate (IP ), which lead to activation of PKC/Ras and calciumdependent signaling pathways, respectively
Summary
8. Gigoux M, Shang J, Pak Y, et al.: Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase. Zeng H, Cohen S, Guy C, et al.: mTORC1 and mTORC2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation. Inabe K, Kurosaki T: Tyrosine phosphorylation of B-cell adaptor for phosphoinositide 3-kinase is required for Akt activation in response to CD19 engagement. Troutman TD, Hu W, Fulenchek S, et al.: Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt. Proc Natl Acad Sci U S A. Chen HH, Händel N, Ngeow J, et al.: Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells.
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