Mechanism of tolerance induction.

Abstract

The randomly generated T-cell repertoire is shaped by two processes that occur in the thymus, positive and negative selection (1-5). Positive selection is responsible for generating a T cell repertoire that has the ability to recognize antigenic peptides in association with self major histocompatibility complex (MHC) molecules. The other process is called negative selection, and assures that tolerance for self-antigens is achieved. During negative selection, potentially autoreactive T cells (i.e. those with high affinity for “self” antigens presented on self-MHC molecules) are actually deleted from the T cell repertoire (2,6,7) or are clonally inactivated (1,8). “Self” is defined here as those self or foreign antigens which are present in the thymus at the moment of selection, a prime moment for which appears to be the early neonatal period: Neonatally thymectomized mice develop a variety of tissue-specific autoimmune diseases later in life (9,10). Although factors controlling these autoimmune diseases are poorly understood, defects in clonal inactivation and clonal deletion have been assigned to be the major cause of autoimmune diseases (9,11,12). In the context of the present definition of self, neonatal virus infection of the thymus results in specific viral peptides being presented as self-antigens, resulting in tolerance for foreign peptides (see below).