Without Brca1, T cells are lacking in numbers and maturity, but surprisingly not because of a lack of repair of rearranged TCR genes. The defects involve more than one p53-dependent mechanism. ceed through a series of trials designed to ensure that those clones guilty of the capacity to initiate an autoimmune catastrophe are punished by death. It is thought that autoimmunity manifests when such “forbidden clones” escape the death sentence and instead survive to initiate their path of destruction. Precursors of T cells arise in the bone marrow and then make their way to the thymus where their maturation and trials commence. During the next few days the cell rearranges the segments of its T cell receptor (TCR) genes, a process which requires effective DNA repair and expression of the TCR proteins (first trial). The T cell receptor protein must react with ligands (major histocompatibility molecules bearing antigenic peptides in the thymus, usually derived from self proteins) with an intermediate affinity—one high enough to ensure the signaling required to maintain the cell’s survival (second trial) but below the threshold necessary for induction of an activation-induced apoptotic pathway (third trial). Failure in any of these trials ensures an automatic death penalty. These trials ensure that maturing T cells can generate effective immune responses without inadvertantly responding to peptides from self pro-