All PI3Kinase signaling is not mTOR: dissecting mTOR-dependent and independent signaling pathways in T cells

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.

Keywords: CD4 T cells; PI3K; effector function; mTOR pathway; tolerance.

Figure 1

PI3K signaling results in the activation of both mTOR-dependent and independent pathways in T cells. A schematic representation of PI3K signaling is shown demonstrating mTOR-independent and mTOR-dependent signaling cascades. Lines with arrows indicate activating signals and lines with bars indicate inhibitory signals. Importantly, this graphic does not include all of the nuanced inputs that are discussed in the text. Rather, these pathways represent connections and not absolute requirements for signaling. For example, while elimination of p110δ or all PI3K regulatory subunits leads to decreased NF-κB, such a deficit can be overcome by the addition of CD28 signaling. Overall, PI3K-induced mTOR-independent signaling can influence both the activation and inhibition of T cells as well as the generation and function of Tregs. The PI3K-induced mTOR-dependent pathways can influence CD4 effector differentiation and function as well as inhibit the generation of Tregs.