Activation by estrogen of the number and function of forbidden T-cell clones in intermediate T-cell receptor cells.

When estrogen (1 mg/mouse) was subcutaneously administered once into mice, the number of liver MNC increased but the number of thymocytes decreased profoundly from Day 3 to Day 20. Phenotypic characterization revealed that the proportion of intermediate (int) TCR cells with IL-2 receptor beta-chain (IL-2R beta) was elevated in both the liver and the thymus. Attention was then focused on how forbidden clones were distributed among various T-cell subsets, including IL-2R beta+ int TCR cells and IL-2R beta-high TCR cells. IL-2R beta+ int TCR cells are generated through the extrathymic pathway in the liver and an alternative intrathymic pathway, whereas IL-2R beta- high TCR cells are generated through the mainstream of T-cell differentiation in the thymus. It was demonstrated that forbidden clones, V beta 3+ and V beta 11+ cells, in BALB/C mice (Mls-1b2a) were confined to IL-2R beta+ int TCR cells, irrespective of the administration of estrogen. Interestingly, the proportion of forbidden clones among int TCR cells increased in the liver but decreased in the thymus after the administration of estrogen. Liver MNC that contained a high level of forbidden clones showed unexpected high levels of spontaneous proliferation and of the proliferative response to immobilized anti-V beta mAb (even in the combination of forbidden clone stimulations). The present results reveal that the levels of both int TCR cells and forbidden clones that induce hepatocyte damage preferentially increase in the liver, one of the prime target organs in autoimmune diseases, when estrogen is administered.