Self-Nonself Discrimination by Developing and Mature T Cells

Abstract

The question of self-nonself discrimination by the immune system is still awaiting a complete solution. The problem was recognized long ago, and Owen’s observation (1945) [1] in dizygotic cattle twins which were chimeric with regard to their blood cells indicated that self tolerance was acquired rather than inherited. Ideas by Burnet and Fenner (1949) [2] which were reinforced by Ledenberg (1963) [3] offered a simple-possibly too simple-solution to the problem of self tolerance: it was argued that clones of lymphocytes, each bearing a distinct antigen receptor, go through an early phase in development in which contact with antigen is lethal rather than inducing effector function. Thus, tolerance to self was thought to be due to the elimination of self reactive clones early during their development. This concept had two weaknesses in explaining all self tolerance. First, it was difficult to imagine that all self antigens could reach developing lymphocytes in primary lymphoid organs. Second, considering the enormous diversity of antigen receptors themselves, it was difficult to see how deletion of lymphocytes induced by diverse receptors on other lymphocytes would leave anything substantial behind fit to deal with foreign antigens [4].