Emerging studies evidenced a role of IL-22 and IL-22-producing T cells, such as Th17 and Th22 cells, in the pathophysiology of several inflammatory and autoimmune diseases. Therefore, the identification of stimulatory molecules and associated signalling pathways regulating IL-22 production and the amplification of specific IL-22-producing T cell subsets may provide novel therapeutic targets for inflammatory and autoimmune diseases.
The major goal of this project is to provide biological bases for single or combined immunotherapeutic approaches targeting CD28-associated class 1A phosphatidylinositol 3 kinase (PI3K) in order to dampen IL-22 production and IL-22-producing T cell amplification. CD28 is a crucial costimulatory receptor necessary for full T cell activation that, in the human system, emanates TCR-independent autonomous signals, which account for its critical role in regulating pro-inflammatory cytokine/chemokine production. For instance, we have demonstrated that human CD28 stimulation is able to promote the production of pro-inflammatory cytokines in peripheral blood CD4+ T cells from healthy subjects as well as Multiple Sclerosis and Type 1 Diabetes patients. More recently we also found that CD28 stimulation up-regulates IL-22 gene expression and secretion. By using specific inhibitory drugs, we also observed that the up-regulation of IL-22 is dependent on CD28-mediated PI3K activation.
Starting from the above reported evidences, the present project will be aimed to characterize the role of CD28 and associated class 1A PI3K in the regulation of IL-22 expression and IL-22-producing T cell subset amplification.
To reach this goal we will proceed with the following tasks:
Task 1. Role of CD28 and associated class 1A PI3K in the regulation of IL-22 production and IL-22-producing T cell amplification.
Task 2. Characterization of the signalling pathways and transcription factors regulating CD28-mediated transcription and secretion of IL-22.
