Regulatory role of phosphoinositide 3-kinase in immune response

We have previously shown that phosphoinositide 3-kinase (PI3K) activity is important in the balance between Th1 and Th2 responses. Lack of PI3K resulted in the impaired host immune response against nematode infection due to decreased Th2 responses. In contrast, PI3K deficiency enhanced Th1 responses and increased the host immune response against Leishmania major infection. Studies on the regulatory mechanisms of Th1/Th2 induction by PI3K have revealed that PI3K negatively regulates production of interleukin (IL)-12, a crucial cytokine for Th1 induction, from dendritic cells (DCs). Numerous stimuli inducing IL-12 production concomitantly activate PI3K in DCs, and both PI3K−/− and PI3K inhibitor-treated DCs demonstrated increased IL-12 production. Our findings indicate the presence of negative feedback mechanisms for IL-12 production during DC activation that likely contribute to the prevention of excessive Th1 polarization causing undesired immune responses. This novel mechanism at the same time highlights the importance of negative regulatory signaling and raises possible therapeutic strategies targeting such signal transduction cascades in innate immune system.