What do we know about the mechanisms of elimination of autoreactive T and B cells and what challenges remain.

Tolerance to self-antigens within the adaptive immune system is safeguarded, at least in part, through deletion of autoreactive T and B lymphocytes. This deletion can occur during the development of these cells in primary lymphoid organs, the thymus or bone marrow, respectively, or at the mature stage in peripheral lymphoid tissues. Deletion of autoreactive lymphocytes is achieved to a large extent through apoptotic cell death. This review describes current understanding of the mechanisms that mediate apoptosis of autoreactive lymphocytes during their development in primary lymphoid organs and during their activation in the periphery. In particular, we discuss the roles of the proapoptotic Bcl-2 family member Bim and the small family of Nur77-related transcriptional regulators in lymphocyte negative selection. Finally, we speculate on the processes that may lead to the activation of Bim when antigen receptors are activated on autoreactive T or B cells.