Our results demonstrate a new influence of PI3K on human T cell differentiation that is unrelated to its lipid-kinase activity and suggest that T<sub>FH</sub> should be monitored in APDS patients.
The activated phosphoinositide 3-kinase δ syndrome (APDS), also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI), is a combined immunodeficiency syndrome caused by gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes <i>PIK3CD</i> (encoding p110δ: APDS1 or PASLI-CD) and <i>PIK3R1</i> (encoding p85α: APDS2 or PASLI-R1).
In this review, we discuss data pertaining to CD8<sup>+</sup> T cell function in APDS/PASLI, including increased cell death, expression of exhaustion markers, and altered killing of autologous EBV-infected B cells, and how these and other data on PI3K provide insight into potential cellular defects that prevent clearance of chronic infections.
There are two classes of APDS: APDS1 that arises from p110δ mutations that are analogous to oncogenic mutations found in the broadly expressed p110α subunit and APDS2 that occurs from a splice mutation resulting in p85α with a central deletion (Δ434-475).
Heterozygous gain of function mutations in the gene encoding p110δ subunit of PI3K have been recently associated with activated PI3K-δ syndrome (APDS), a novel combined immune deficiency characterized by recurrent sinopulmonary infections, lymphopenia, reduced class-switched memory B cells, lymphadenopathy, CMV and/or EBV viremia and EBV-related lymphoma.
Autosomal dominant gain-of-function mutations in PIK3R1 encoding for the regulatory subunit (p85α, p55α, and p50α) of Class IA phosphoinositide 3-kinase (PI3K) result in the activated PI3Kδ syndrome (APDS) type 2 characterized by childhood-onset combined immunodeficiency, lymphoproliferation, and immune dysregulation.
Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activated PI3Kδ syndrome (APDS; also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI)).