The role of the thymus in tolerance

Abstract

The thymus serves as the central organ of immunologic self-nonself discrimination. Thymocytes undergo both positive and negative selection, resulting in T cells with a broad range of reactivity to foreign antigens but with a lack of reactivity to self-antigens. The thymus is also the source of a subset of regulatory T cells that inhibit autoreactivity of T-cell clones that may escape negative selection. As a result of these functions, the thymus has been shown to be essential for the induction of tolerance in many rodent and large animal models. Proper donor antigen presentation in the thymus after bone marrow, dendritic cell, or solid organ transplantation has been shown to induce tolerance to allografts. The molecular mechanisms of positive and negative selection and regulatory T-cell development must be understood if a tolerance-inducing therapeutic intervention is to be designed effectively. In this brief and selective review, we present some of the known information on T-cell development and on the role of the thymus in experimental models of transplant tolerance. We also cite some clinical attempts to induce tolerance to allografts using pharmacologic or biologic interventions.

Figure 1

Positive and negative selection in the thymus. Thymocytes enter the cortex and undergo T cell receptor (TCR) gene rearrangement and display both CD4 and CD8. These cells interact with cortical thymic epithelial cells (CTEC) and undergo apoptosis unless they receive a survival signal generated via TCR/self-peptide—MHC interaction. Positively selected thymocytes progress to single-positive CD4 or CD8 cells and enter the medulla. High-avidity TCR/self-peptide—MHC ligation in the presence of medullary thymic epithelial cell (MTEC) or dendritic cell (DC) co-stimulatory molecules in the medulla lead to negative selection of self-reactive thymocytes. (Modified with permission from Palmer E. Negative selection--clearing out the bad apples from the T-cell repertoire. Nat Rev Immunol 2003; 3 (5): 383.)