**3.1 RAGE and T cells**

Immune tolerance involves a diverse range of processes that prevent potentially harmful immune responses against self-antigens. Given that T1DM is a T cell mediated autoimmune disease, a key event in its development is the failure in the mechanisms of central tolerance, which allows for self-reactive T lymphocytes to escape deletion by the immune system. Once in the periphery, these effector T lymphocytes can exert deleterious effects with CD4+ T lymphocytes believed to be important initiators and progressors of autoimmunity. Upon encounter of islet-antigen presented by dendritic cells (DCs), CD4<sup>+</sup> T lymphocytes become activated which promotes and perpetuates the diabetogenic process. The reasons as to why islet autoantigens are specifically presented to the immune system by DCs to amplify immune responses remains to be fully elucidated. Migration of DCs to pancreatic lymph nodes and isletantigen presentation there amplifies recruitment and activation of CD4<sup>+</sup> and CD8+ T lymphocytes.

An extensive pancreatic β- cell loss or loss of function is hallmark of T1DM. It is now well appreciated that autoreactive T cell are amongst key players in this process. CD4+ T cells are thought to be initiators of the disease providing help for B cells in "auto"antibody production as well as enhancing effector activity of CD8+ T cells and islet-resident macrophages. CD8<sup>+</sup> effector T cells are considered to cause pancreatic islet destruction and commonly dominate islet infiltrates [31–33].
