SELF-REACTIVE FORBIDDEN CLONES ARE CONFINED TO PATHWAYS OF INTERMEDIATE T-CELL RECEPTOR CELL-DIFFERENTIATION EVEN UNDER IMMUNOSUPPRESSIVE CONDITIONS

It is believed that self-reactive forbidden T-cell clones are generate d by 'failure' of the pathway of T-cell differentiation in the thymus, if it is disturbed. We examined how such forbidden clones are generat ed under immunosuppressive conditions. Mice were treated with an injec tion of deoxyspergualin, FK506, or cycloporin A. From day 3, the numbe r of cells yielded by various organs decreased. Because of the resista nce of intermediate (int) T-cell receptor (TCR) cells (i.e. TCRint cel ls), they became more prominent ia proportion than TCRhigh cells, TCRh igh cells are conventional T cells generated through I-he mainstream i n the thymus, whereas TCRint cells are primordial T cells generated by the extrathymic pathway or an alternative intrathymic pathway. Simila r to untreated mice, forbidden V beta 3(+) and V beta 11(+) clones in C3H/He (Mls-l(b)2(a)) mice were confined to TCRint cells after treatme nt; there was no leakage of forbidden clones into TCRhigh cells in the thymus and periphery. In parallel with the increase in the proportion of TCRint cells, the proportion of forbidden clones also increased un der immunosuppressive slates, especially in the liver. Liver mononucle ar cells isolated from treated mice still had the potential to mediate autologous killing. The present results suggest that the generation o f self-reactive clones is highly restricted to the pathways of TCRint cell differentiation even under immunosuppressive conditions.