The cellular destruction in organ specific autoimmune diseases is clearly mediated by the cellular arm of the immune system. This process is also often associated with a humoral response characterized by the production of autoantibodies, which often precedes the clinical onset of the disease. There is also accumulating evidence that beside clonal deletion and anergy, regulatory T cells−mediated dominant control of self−reactive lymphocytes might contribute to the maintenance of immunologic self−tolerance. Whether autoreactive T cells became pathogenic because of intrinsic defects or as a result of an impaired immunoregulation is still largely unknown.

This project aim at investigating the phenotype and regulation of autoreactive T cells in autoimmune diseases. In the first part of the project we will determine the frequency of autoreactive T cells and characterize their cellular phenotype in patients at disease onset. Moreover, we are investigating the impact of maternal autoimmunity on fetal immune system and on the future risk to develop organ specific autoimmune diseases. The possibility to isolate antigen−specific T cells will allow us to study the regulation of self−antigen specific T cells. Three different possibilities, not mutually exclusive, will be studied in details: a) resistance of autoreactive T cells to immune mediated suppression; b) a defective inhibitory function of T reg (decreased suppression function); c) intrinsic defect of antigen presenting cells (aberrant Ag presentation, defective costimulation).

Successful induction of long−term tolerance in autoimmune diseases depends upon the identification of susceptible individuals before T cell priming and tissue destruction has become irreversible. New assays that will enable to study the emergence of autoreactive T cells are therefore highly demanded and crucial to improve disease prediction and to follow immunological changes during immune−intervention trials. Understanding how the immune system is regulated and which are the cellular mechanisms involved in tolerance induction and diabetes prevention will lead to the development of novel and better therapeutic strategies.