PI3K at the crossroads: choosing B-cell activation or tolerance

Phosphoinositide 3-kinase (PI3K) mediates signaling downstream of many receptors expressed by B cells. Studies in both mice and humans have shown that PI3K plays a critical role in B-cell development, activation, and tolerance. Indeed the key role of PI3K in regulating activation versus tolerance is demonstrated by patients with genetic variants that cause increased PI3K signaling, which results in an immune dysregulatory disorder characterized by a range of manifestations including lymphoproliferation and autoantibody production. Interestingly, PI3K signaling also plays an essential role in metabolic reprogramming. This review examines the role of PI3K signaling in regulating both central and peripheral B-cell tolerance and how dysregulation of these pathways can lead to production of autoantibodies. It also briefly explores PI3K-mediated changes in metabolism and considers how this may contribute to PI3K-mediated control of B-cell activation and tolerance.