Self/nonself discrimination among immunoregulatory (CD4) T cells

This review covers work on immunological tolerance from 1962 up to the present, focusing on the Th, CD4+ compartment of the immune system. The principle mechanism of tolerance is identified as deletion, occurring centrally and in the periphery. In the periphery, deletion is the normal response of CD4 T cells to soluble monomeric proteins that occurs when activation (mainly of dendritic cells) is avoided. Thus activation and the signals which induce it are crucial to understanding S/NS discrimination, as has long been known. The thymus is important as the site where new T cells first see self-antigens, and as one largely shielded from activation, although deletion in the thymus and the periphery has the same threshold. The relative contribution of dendritic cells and developing T cells to deletion in the thymus remains unclear. Activation induced cell death, containment, anergy and deviation constitute subsidiary mechanisms, and sequestration/neglect is important in limiting the scope of deletion.