A ROLE FOR CLONAL INACTIVATION IN T-CELL TOLERANCE TO MLS-1A

CLONAL deletion plays a major part in the maintenance of natural self-tolerance in both normal1-5 and transgenic6-9 mice. Self antigens that are expressed in the thymus result in the physical elimination of autoreactive thymocytes at a particular stage in their development. For example, the majority Vβ6- and Vβ8.1-bearing T cells that recognize the minor lymphocyte-stimulating antigen, Mis-1a (ref. 10), are clonally deleted in the thymuses of normal mice and transgenic mice expressing Mis-1a (refs 2, 3, 9). In contrast, a very different mechanism of tolerance involving the functional inactivation, but not elimination, of autoreactive cells, termed clonal inactivation or clonal anergy, has been implicated in some experimentally manipulated systems of tolerance11-15. To test further the mechanisms involved in self-tolerance, we have generated transgenic mice expressing a Vβ 8.1 beta chain on >95% of peripheral T cells and have tested tolerance to Mis-1a in these mice. Surprisingly, a significant fraction of the CD4+ peripheral cells that survived deletion were non-responsive in vitro to any stimulus tested. Naturally occurring tolerance to a self antigen expressed in the thymus can thus be mediated by clonal anergy, as well as by clonal deletion. © 1990 Nature Publishing Group.