Pro-inflammatory T lymphocytes play a critical role in the pathophysiology of several autoimmune diseases. Emerging data indicate that cellular metabolism regulates immune cell functions and differentiation. In particular, the amplification of inflammatory Th17 cells and reduction of suppressive regulatory T cells (Treg) represent the main abnormalities in several autoimmune diseases. Thus, the identification of stimulatory molecules and associated signalling pathways coordinating the metabolic processes that maintain/amplify the inflammatory phenotype of peripheral T cells, may be useful for the development of new therapeutic opportunities in inflammatory/autoimmune diseases.
CD28 is a crucial costimulatory receptor necessary for full T cell activation. CD28 is also able to regulate T cell metabolism by enhancing nutrient uptake, aerobic glycolysis and anabolic pathways. Indeed, CD28 binds class 1A PI3K that in turn recruits and activate the PDK1/Akt/mTOR pathways. By up-regulating glucose uptake and favouring the metabolic switch to aerobic glycolysis and the differentiation of specific Th cell subsets in the periphery, in particular Th17 cell differentiation, the PI3K/PDK1/Akt/mTOR pathway is crucial in regulating the metabolism of activated T lymphocytes. Thus, CD28 stimulation may provide TCR-independent signals, which activate PI3K/PDK1/Akt/mTOR and the metabolic processes regulating the inflammatory T cell responses. For instance, we have recently found that CD28-associated class 1 PI3K regulates the amplification of specific pro-inflammatory T cell subsets producing specific cytokines and chemokines in multiple sclerosis (MS) and type 1 diabetes (T1D) patients.
Starting from the above reported evidences, the present project will be aimed to characterize the role of CD28 and associated PI3K/PDK1/Akt signalling pathways in the modulation of the metabolic programs regulating pro-inflammatory T cell responses.