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.
Emerging data indicate that cellular metabolism regulates immune cell functions and differentiation. In particular, the growth, survival, differentiation and inflammatory functions of T lymphocytes depend on a dramatic increase in glucose metabolism (20). Indeed, glucose represents a primary source of energy production (ATP) in proliferating T lymphocytes and may be metabolized through two primary processes: glycolysis and the tricarboxylic acid (TCA) cycle. Glycolysis occurs in the cytoplasm and converts glucose to pyruvate, thus generating 2 molecules of ATP. TCA cycle occurs in the mitochondria and fuels the oxidative phosphorylation (OXPHOS). The main source of energy for TCA cycle is represented by lipids, from which oxidation (fatty acid oxidation, FAO) T cells obtain 106 molecules of ATP, compared to the 32 generated by the oxidation of one molecule of glucose. Specific metabolic pathways have been described to control T cell function and differentiation (3). Elevated glycolysis associates with the differentiation and functions of inflammatory Th17 cells (6). By contrast, FAO metabolism constrains Th17 and promotes the differentiation of suppressive regulatory T cells (Treg) (21, 22). However, more recent data suggest that impaired glycolysis may also be responsible for altered suppressive activity of Treg in autoimmune disease such as Multiple Sclerosis (MS) (23).
The present project will assess the contribution of CD28, as a TCR-independent signalling unit, in activating PI3K/PDK1/Akt and the metabolic processes regulating pro-inflammatory T cell functions. For instance, our recent data evidenced that CD28 stimulation itself up-regulates the expression of pro-inflammatory cytokines/chemokines and that class 1A PI3K is involved in CD28 pro-inflammatory function (8, 14).
The characterization of CD28 and associated class 1A PI3K/Akt/mTOR signalling pathway in coordinating the metabolic processes that maintain/amplify the inflammatory phenotype of peripheral T cells, may be useful for the development of new therapeutic opportunities.