Abstract
The mechanistic target of rapamycin (mTOR) is emerging as playing a central role in regulating T cell activation, differentiation, and function. mTOR integrates diverse signals from the immune microenvironment to shape the outcome of T cell receptor (TCR) antigen recognition. Phosphatidylinositol 3-kinase (PI3K) enzymes are critical mediators of T cell activation through their generation of the second messenger phosphatidylinositol (3,4,5) triphosphate (PIP3). Indeed, PIP3 generation results in the activation of Protein Kinase B (PKB, also known as AKT), a key activator of mTOR. However, recent genetic studies have demonstrated inconsistencies between PI3K disruption and loss of mTOR expression with regard to the regulation of effector and regulatory T cell homeostasis and function. In this review, we focus on how PI3K activation directs mature CD4 T cell activation and effector function by pathways dependent on and independent of mTOR signaling. Importantly, what has become clear is that targeting both mTOR-dependent and mTOR-independent PI3K-induced signaling distally affords the opportunity for more selective regulation of T cell differentiation and function.
Highlights
The Class IA phosphatidylinositol 3-kinase (PI3K) family consists of a heterodimeric complex of one of the 110-kDa catalytic subunits (p110α, β, δ) with a regulatory subunit (p85α, p55α, p50α, p85β, and p55γ), reviewed in Kane and Weiss (2003); Okkenhaug and Vanhaesebroeck (2003)
We focus on how PI3K activation directs mature CD4 T cell activation and effector function by pathways dependent on and independent of mechanistic target of rapamycin (mTOR) signaling
Through use of dose responses to selective PI3K inhibitors, Sauer et al attribute FoxP3 induction to inhibition of PI3Kα and δ upstream of AKT and mTOR. These findings raise a paradox: small molecule inhibitors of PI3K, AKT, and mTOR all result in a similar phenotype, promoting induction of FoxP3 expression following activation of naïve CD4 T cells, but the phenotypes of mice with genetic lesions resulting in loss of T cell PI3K expression demonstrate inefficient Treg production and decreased Treg function
Summary
The Class IA phosphatidylinositol 3-kinase (PI3K) family consists of a heterodimeric complex of one of the 110-kDa catalytic subunits (p110α, β, δ) with a regulatory subunit (p85α, p55α, p50α, p85β, and p55γ), reviewed in Kane and Weiss (2003); Okkenhaug and Vanhaesebroeck (2003). This partial preservation of CD3/CD28-induced signals including some mTOR activation may explain why proliferation is only slightly reduced while IL-2 and IFN-γ are more profoundly suppressed, which would not be predicted by the PI3K and rapamycin inhibitor studies described above and differs from the phenotype following T cell specific deletion of mTOR.
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