Thymus and tolerance. Is regulation the major function of the thymus?

This paper will serve as a contribution to the current reassessment of the relative roles of clonal selection and regulation in specific immunologic tolerance. We review basic studies in the Waksman laboratory that first established the importance of the thymus in tolerance and the possible contribution of regulatory cells generated in the thymus to self-tolerance. Experimental evidence is presented to suggest that there exists a wide range of immunoregulatory mechanisms, many of which deserve more intensive investigation in relation to the tolerance question. These include regulation based on idiotype-specific recognition, multiple forms of immune deviation, two well-described and quite distinct forms of T-cell receptor alphabeta "suppressor cell", and several regulatory systems involving multiple cells acting in concert. We do not comment on more recently described regulatory cells, such as certain gammadelta T-cell subsets, natural killer T cells, CD4-CD8- T cells, and others. Basic studies in our laboratory and in other laboratories pointed to antigen-presenting cells (APC) generated in the thymus as possible mediators of tolerance. Certain cytokines, first described in our laboratory, including lymphotoxin and the "inhibitor of DNA synthesis" produced by T cells and interleukin-1 produced by macrophages, also may act as significant components of regulatory systems. The rapid entry of exogenous and self-antigens into the thymus and the free migration of specific regulatory T cells and of APC in both directions between thymus and periphery are also stressed.