Mechanisms of activation and regulation in autoimmunity

The aim of this thesis is to understand the mechanisms of break of tolerance in autoimmunity and the regulatory pathways that control self-reactive T cells and their peripheral activation. To address these questions in vivo, I have fully characterized the humanized transgenic TAZ10 mice which express a human self-reactive T Cell Receptor (TCR) isolated from the thyroid infiltrate of a patient. The TCR is specific for a cryptic epitope of a main thyroid auto-antigen, Thyroid Peroxidase (TPO) and is positively selected on both CD4+ and CD8+ T cells. I found that the transgenic T cells are functional in vitro and are highly activated. As a result, TAZ10 mice spontaneously develop chronic autoimmune thyroiditis with clinical, histological and hormonal changes that closely resembles human Hashimoto’s disease. In TAZ10 Rag-/- mice, CD4+ T cells are selected both as pathogenic effector and as naturally arising CD4+CD25highFoxp3+ regulatory T cells (Treg). This has allowed us to study the role of antigen-specific Treg in autoimmunity. These TPO-specific Treg suppress proliferation of effector T cells in vitro and delay the onset of disease in vivo, yet they fail to fully protect animals from thyroiditis. This is because TAZ10 Treg die by AICD at the sites of inflammation. I have also showed that thymic selection of TPO-specific Treg in TAZ10 Rag-/- mice occurs only in H2-Ak mice, as TAZ10 mice backcrossed onto H2-Ab Rag-/- do not present the population of Treg. In this thesis I will discuss the mechanisms underlying this finding. In TAZ10 Rag-/- mice, I have also characterized another population of regulatory T cells, the αβTCR+CD4-CD8- Double Negative (DN) T cells, which suppress proliferation of effector T cells with a mechanism FAS-FASL mediated. In this thesis, I have characterized the mechanisms of cellular activation and regulation of a novel humanized mouse model of spontaneous autoimmune thyroiditis. I have showed the pathogenic role in vivo of human self-reactive T cells and described the regulatory networks operated by DN T cells and Foxp3+ naturally arising Treg.