T-cell education in autoimmune diabetes: teachers and students.

Type 1 diabetes mellitus is a classical example of a T-cell-mediated autoimmune disease. Several aberrations in immune regulation have been described in both human diabetes patients and animal models of type 1 diabetes. In this review, we summarize how proposed immune defects might be implicated in the loss of T-cell tolerance towards self in autoimmune diabetes in humans, nonobese diabetic (NOD) mice and Biobreeding (BB) rats. For this purpose, we will discuss the tolerance-inducing mechanisms that an autoreactive T cell should encounter from its genesis to its pathogenic role in the pancreas, in order of appearance. These comprise central tolerance mechanisms (i.e. positive and negative selection in the thymus) and those mechanisms operative in the periphery (i.e. activation-induced cell death and regulatory T cells).