Peripheral tolerance is mediated by deletion, anergy and suppression as well as by “neglect” or “ignorance,” acting on autoreactive lymphocytes after they exit the primary organs. In general, lymphocyte activation requires two signals, one delivered by the antigen receptor (T-cell antigen receptor or surface immunoglobulin) and second, a co-stimulatory signals. For T-cell activation, this co-stimulatory signal is delivered by the interaction of molecules expressed on the surface of professional antigen-presenting cells or B cells, such as CD80 and CD86, which interact with CD28 (or other receptors) on the T-cell surface. In the case of B-cells, the co-stimulatory signal is delivered by CD40 ligand, a surface protein expressed by activated helper T cells that interacts with CD40 on the surface of B lymphocytes. In the absence of a co-stimulatory signal, engagement of the T- or B-cell antigen receptor leads to a state of anergy (the inability of the lymphocyte to respond to its specific antigen).