T cell regulation in Juvenile Idiopathic Arthritis : Controlling chronic inflammation by pulling the right strings

Understanding the complex cellular and molecular mechanisms that regulate the immune response remains one of the major challenges in immunology. A key question is how the immune system is regulated in order to control a protective immune response and prevent chronic and destructive immunopathology. Within the adaptive immune system CD4+ T cells are keyplayers in the initiation and orchestration of immune responses. However, there is now increasing evidence that subsets of CD4+ T cells are also important negative regulators. Amongst these, the so-called naturally occurring CD4+CD25+ Tregs and IL-10 producing Tr1 cells are the best characterized. The ability of regulatory T cells (Tregs) to control many facets of the immune response suggests that they might be used as targets for new therapeutic strategies. In the first part of this thesis we explored the presence and functionality of different subsets of Tregs in Juvenile Idiopathic Arthritis (JIA). We identified and characterized self heat shock protein 60 (HSP60) specific T cells (chapter 2) and we studied the frequency, phenotype and functionality of naturally occurring CD4+CD25+ Tregs in JIA patients (chapter 3). Subsequently, we explored the role of human HSP60 in the induction and function of CD4+CD25+ Tregs using PBMC of healthy controls and tried to further classify the human HSP60 specific T cells (chapter 4). In the second part of this thesis we evaluated the safety and effectiveness of Autologous Stem Cell Transplantation (ASCT) for refractory JIA by studying 34 JIA patients transplanted in 9 different transplantation centers within Europe (chapter 5). Furthermore, we explored the mechanisms that are attributable to the induction of tolerance by ASCT and identified CD4+CD25+ Tregs as one of the keyplayers in this induction (chapter 6). Taken together the studies described in this thesis may contribute to our understanding of the pathophysiology of JIA as well as of the physiology of regulatory immune responses in general. We identified different subsets of Tregs as crucial players in the tolerization process. Furthermore, it identified human HSP60 being the first known physiological human antigen, naturally present at inflammatory sites and able to activate Tregs. This knowledge may be pivotal in designing the new immunoregulatory strategies for JIA and other autoimmune diseases