The Role of the PI3K Signaling Pathway in CD4(+) T Cell Differentiation and Function

Jonathan M Han, Scott J Patterson, Megan K Levings, Jonathan M Han, Scott J Patterson, Megan K Levings

Abstract

The relative activity of regulatory versus conventional CD4(+) T cells ultimately maintains the delicate balance between immune tolerance and inflammation. At the molecular level, the activity of phosphatidylinositol 3-kinase (PI3K) and its downstream positive and negative regulators has a major role in controlling the balance between immune regulation and activation of different subsets of effector CD4(+) T cells. In contrast to effector T cells which require activation of the PI3K to differentiate and mediate their effector function, regulatory T cells rely on minimal activation of this pathway to develop and maintain their characteristic phenotype, function, and metabolic state. In this review, we discuss the role of the PI3K signaling pathway in CD4(+) T cell differentiation and function, and focus on how modulation of this pathway in T cells can alter the outcome of an immune response, ultimately tipping the balance between tolerance and inflammation.

Keywords: AKT; CD4+ T cells; FOXP3; PI3K; mTOR; rapamycin; regulatory T cells.

Figures

Figure 1
Figure 1
The role of PI3K/AKT signaling pathway in Tregs. Arrow indicates activating phosphorylation; line with a perpendicular line at the end indicates inhibitory phosphorylation; line with a circle at the end indicates dephosphorylation; dashed line indicates resulting outcome of signaling. Green represents components of the PI3K/AKT pathway which have been shown to be beneficial for Treg function and/or development. On the contrary, red indicates molecules with activity thought to be inhibitory for Treg function and/or development.
Figure 2
Figure 2
Intracellular “tug-of-war” determines T cell fate. Green arrow indicates activation of PI3K signaling; red arrow indicates inhibition of PI3K signaling. The strength of PI3K signaling is influenced by opposing activation and inhibitory signals that are integrated from extracellular stimuli such as co-stimulation, co-inhibition, and cytokines/adipokines. Ultimately, the outcome of this “tug-of-war” determines whether a T cell becomes a Treg to mediate tolerance, or inflammatory Th subsets to mediate immunity.

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