T CELLS IN CHRONIC INFLAMMATORY ENVIRONMENTS: there's more than meets the eye

Abstract

Chronic inflammatory diseases (CID) are characterized by a chronic and recurrent state of local inflammation mediated by the immune system. T cells are essential component of the immune system, whose imbalanced actions contribute to the pathology of CID. Aim of this thesis was to dissect how inflammation ongoing at the target sites of CID influences T cell development and functions, with a particular focus on Juvenile Idiopathic Arthritis (JIA). In this thesis we describe that: (i) CD8 T cells localized at the site of inflammation of JIA patients escape suppression by regulatory T cells via autocrine release of IFN-g; (ii) PD-1+CD8 T cells are elevated at the site of inflammation of CID, display an inflammatory and activated profile, and show features of self-reactivity and local adaptation; (iii) the cytokine IL-27, elevated at the site of inflammation of JIA, sustains the survival and pro-inflammatory features of IFN-g-producing CD4 T cells. Then we attempted to move to the clinic by developing a protocol for the generation of a subset of regulatory T cells (i.e. Tr1) from patients with kidney failure -characterized by a state of chronic peripheral inflammation- for infusion in living donor kidney transplanted patients to ultimately obtain long-term graft acceptance. Finally, we discussed the need of a specific training program to develop Translational Medicine Professionals by providing education as well as a long-lasting network of peers with the final goal to develop clinically applicable products and technologies.