The why and how of thymocyte negative selection

The generation of T cell receptor (TCR) sequence diversity is the strength of adaptive immunity, yet is also the Achilles’ heel. To purge highly self-reactive T cells from the immune system, generation of diversity has coevolved with a mechanism of negative selection. Recent studies have revealed new insights addressing the why and how of negative selection by examining situations in which negative selection has failed in human and animals models of autoimmunity. Both thymocyte extrinsic and intrinsic mechanisms are required to restrict the TCR repertoire to a non-autoreactive set. Negative selection also ensures that T cells emerge with receptors that are focussed on the peptide moiety of MHC-peptide complexes.