Do PI3-kinase mutations drive T cells insane?

Abstract

The link between the differentiation of effector T lymphocytes and metabolism has become an important area of research. The role played by the phosphoinositide 3-kinase (PI3K)/Akt/mTOR (mammalian target of rapamycin) pathway in this process was recently emphasized by Lucas et al.1 who reported a series of primary immunodeficiency patients with three different germ-line, gain-of-function mutations of the p110δ subunit of PI3K. The patients consistently presented a deficiency in naive T lymphocytes and an accumulation of highly differentiated effector T cells. This phenotype was associated with recurrent respiratory infections and with the reactivation of persistent viruses. The disease was named PASLI (p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency). The same disorder was simultaneously reported by Angulo et al.2 and was named the activated PI3K-δ syndrome (APDS). Although the accumulation of effector T cells in the state of immunodeficiency was somewhat unexpected, the description of this syndrome provides important insight into the regulation of T-cell differentiation and T-cell memory.