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.
The immunopathogenesis of several inflammatory and autoimmune diseases relies on both the amplification and persistence of pro-inflammatory IL-22-producing cells, including Th17 and Th22 cells. Therefore, the characterization of the mechanisms and molecules regulating the production of IL-22 and the expansion of pro-inflammatory IL-22-producing cells could represent an important goal of the ongoing research in inflammation and autoimmunity. 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 isolated from multiple sclerosis and type 1 diabetes patients. More recently we also found that CD28 stimulation up-regulates IL-22 gene expression and secretion in peripheral CD4+ T cells. By using specific inhibitory drugs, we also observed that the up-regulation of IL-22 was dependent on CD28-mediated PI3K activation. These data strongly suggest that abnormalities resulting in the hyperactivity of CD28-associated class 1A PI3K may lead to the development and/or exacerbation of inflammation and autoimmunity.
The major goal of this project is to provide biological bases for single or combined immunotherapeutic approaches targeting CD28-associated class 1A PI3K in order to dampen IL-22 production and IL-22-producing T cell amplification. For instance, the availability of oral active forms of class 1A PI3K inhibitors, some of which have entered clinical trials for cancer therapy, inflammation and coronary heart disease, may also circumvent the adverse side effects (e.g. skin indurations and lipoatrophy) related to infusion or injection and may exhibit higher adherence and long-term persistence. This project will provide the in vitro data necessary for the design of more appropriate therapie aimed to target class 1A PI3K for further translation to clinical research in humans.