The PI3K pathway in B cell metabolism

Abstract

B cell growth and proliferation is tightly regulated by signaling through the B cell receptor and by other membrane bound receptors responding to different cytokines. The PI3K signaling pathway has been shown to play a crucial role in B cell activation, differentiation and survival. Activated B cells undergo metabolic reprogramming in response to changing energetic and biosynthetic demands. B cells also need to be able to coordinate metabolic activity and proliferation with nutrient availability. The PI3K signaling network has been implicated in regulating nutrient acquisition, utilization and biosynthesis, thus integrating receptor mediated signaling with cell metabolism. In this review, we discuss the current knowledge about metabolic changes induced in activated B cells, strategies to adapt to metabolic stress and the role of PI3K signaling in these processes.

The PI3K Pathway in Human Disease

“…Several comprehensive reviews have detailed how PI3K signaling is engaged by different receptors to regulate a variety of lymphocyte responses, and how genetic deficiency or hyperactivity of PI3K isoforms can both lead to immunodeficiency (Hawkins and Stephens, 2015; Lucas et al, 2016; Okkenhaug and Vanhaesebroeck, 2003). The roles of mTORC1 and mTORC2 in the metabolic programming and differentiation of effector lymphocytes is another topic that has been thoroughly reviewed (Chi, 2012; Jellusova and Rickert, 2016; Waickman and Powell, 2012). Here we will emphasize and discuss the distinct wiring of PI3K signaling networks in lymphocytes.…”

“…While mTORC1 activity is essential for lymphocyte proliferation and effector subset differentiation, hyperactivation of mTORC1 in T or B cells lacking TSC1 impairs development, homeostasis and function (Jellusova and Rickert, 2016; Pollizzi et al, 2015). These observations support a unifying theme that PI3K/AKT/mTOR activation in lymphocytes is not an on/off switch for adaptive immunity.…”

MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells

“…There is evidence that mTORC2 also plays a role in antibody class switching (Limon et al, 2014) and mature B cell homeostasis (Lee et al, 2013), which may reflect contributions of Akt-Foxo1 signaling to this process. Readers are directed to a recent review on PI3K signaling in B cells for broader discussion of the role of mTOR in these cells (Jellusova and Rickert, 2016), as well as the impact of metabolic regulation on antibody responses by Boothby and Rickert (2017) in this issue.…”

Fine tuning of immunometabolism for the treatment of rheumatic diseases

“…Stimulation of B cells through antigen receptors or Toll-like receptors (TLRs) leads to upregulation of the glucose transporter GLUT1 and glycolysis 24,25 . As in T cells, this metabolic reprogramming is dependent on mTOR signalling, as deficiency of regulatory-associated protein of mTOR (RAPTOR) and mTOR complex I (mTORC1) or alteration of the PI3K pathway disrupts B cell development and activation, and can impair class-switching in germinal centres 26–28 . Ultimately, as an immune response ceases, memory lymphocytes revert to oxidative pathways that are essential to enabling persistence of memory and robust secondary responses 10,12 .…”