UNOPPOSED POSITIVE SELECTION AND AUTOREACTIVITY IN MICE EXPRESSING CLASS-II MHC ONLY ON THYMIC CORTEX

THE normal development of T cells in the thymus requires both positive and negative selection. During positive selection, thymocytes mature only if their T-cell receptors react with some specificity to host maj or histocompatibility complex (MHC) and host peptides. During negative selection, thymocytes die if their T-cell receptors react with too hi gh an affinity to the presenting cell, self MHC, and peptides to which they are exposed. These two processes are important for the developme nt of the T-cell repertoire and the acquisition of self-tolerance, but their precise location and temporal relationship are not known. We ha ve used the keratin 14 (K14) promoter to re-express a class II MHC ant igen (I-A(b)) in class II-negative mice. The transgenic I-A molecule i s expressed only on thymic cortical epithelium; thymic medullary epith elium and bone-marrow-derived cells are I-A negative. CD4(+) cells are positively selected in K14 mice, but clonal deletion does not occur i n K14 mice or in reIB-negative mice, which lack a thymic medulla. The K14 CD4 cells are autoreactive, as they proliferate extensively to and specifically lyse I-A(b)-positive target cells. These autoreactive ce lls make up 5% of the peripheral CD4 T cells, providing an estimate of the minimal frequency of positively selected cells that must subseque ntly undergo negative selection for self-tolerance to be preserved, Th us positive and negative selection occur in anatomically distinct site s.