T Cell Tolerance and Self/Nonself Discrimination

Abstract

T cell tolerance to self antigens is at least partly a reflection of clonal deletion of immature T cells in the thymus. Although it is well accepted that intrathymic tolerance is primarily a reflection of T cell contact with bone-marrow (BM)-derived antigen-presented cells (APC), evidence is presented that thymic epithelial cells (TEC) can contribute to tolerance induction. Studies with thymocytes from BM chimeras suggest that selective contact with antigen on TEC induces clonal deletion of a subset of high-affinity T cells; these cells are primarily responsible for in vivo effector functions such as allograft rejection and induction of lethal graft-versus-host disease. Intrathymic contact with TEC fails to delete the typical low-affinity T cells which mediate cytotoxic responses in vitro when cultured with lymphokines. Deletion of these low-affinity T cells appears to require contact with BM-derived APC. Despite the evidence that self tolerance involves clonal deletion in the thymus, it is often stated that backup mechanisms for tolerance induction must exist in the post-thymic environment, but this has yet to be proved. The competing argument is that normal self/nonself discrimination is solely a reflection of intrathymic tolerance: the failure of T cells to react against tissue-specific antigens is not a reflection of post-thymic tolerance but simply that T cells and tissue-specific antigens are kept segregated.