Chapter 22 - Development of Tolerance to Self in T Lymphocytes

Abstract

Self–non-self discrimination is a hallmark of the lymphocytes of the adaptive immune response. Random gene rearrangements that produce a DNA sequence coding for the T cell receptor and the B cell receptor result in differentiation of lymphocytes that express a large number of antigen-binding specificities, some of which inevitably recognize self. Developing T lymphocytes that potentially react against self must be identified and either eliminated or silenced. In 1949, F. Macfarlane Burnet and Frank Fenner predicted in the clonal selection theory that developing lymphocytes progress through a stage during which they are particularly sensitive to elimination if they interact with self-antigens. Rupert Billingham with Peter Medawar in 1953 confirmed this prediction by demonstrating that unresponsiveness to a foreign antigen can be induced early in the life of an animal by exposing developing lymphocytes to the antigen. These results suggest that a mechanism exists to alter the reactivity of potentially self-reactive lymphocytes. Jacque Miller focused attention on the thymus when he showed in 1961 that removal of this organ in the neonatal period inhibited normal adaptive immune responses. Studies performed during the 1970s and 1980s demonstrated the existence of a two-step process that results in retention of T lymphocytes capable of recognizing antigen presented by self-HLA molecules (positive selection) and the elimination of T lymphocytes that are potentially autoreactive (negative selection).