A Transgenic Window on Self-Reactive T Lymphocytes

Self-tolerance is likely to be mediated by both central and peripheral mechanisms. The major tolerogenic mechanism for T lymphocytes is generally accepted to be the intrathymic negative selection of differentiating self-reactive T cells. This has been shown in situations characterized by a high frequency of T cells specific for a given self antigen, such as a superantigen or some defined cell surface antigen in the case of T-cell receptor (TCR) transgenic mice (reviewed in 1). Nevertheless, there is ample evidence for the existence of potentially autoreactive T cells in the peripheral T-cell pool of healthy individuals and of experimental animals (2,3). These cells escape thymus censorship presumably because they express antigen-specific TCRs of too low an affinity for the self antigen. Alternatively, the self epitope may not form a stable complex with major histocompatibility complex (MHC) molecules in the thymus. Since autoimmunity is rare, mechanisms must operate to hold in check the autoaggressive potential of such escapees. One possibility is that these T cells ignore their autoantigen, either because they cannot penetrate endothelial barriers, or because they cannot be activated as a result of autoantigen recognition on tissue cells that do not express co- stimulator molecules. Alternatively, the autoimmune T cells may be anergized or deleted peripherally by the autoantigen or they could be silenced by immunoregulatory cells.