Intravenous injection of soluble antigen induces thymic and peripheral T-cell apoptosis

The mechanism by which tolerance is induced via systemic administration of high doses of aqueous antigen has been analyzed by using mice transgenic for a T-cell receptor specific for the influenza virus hemagglutinin (HA) peptide comprising amino acids 126-138, After intravenous injection of 750 (but not 75) mu g of HA peptide, a state of hyporesponsiveness was rapidly induced, In the thymus, in situ apoptosis in the cortex and at the corticomedullary junction was responsible for a synchronous and massive deletion of CD4(+) CD8(+) thymocytes, In secondary lymphoid organs, HA-reactive T cells were initially activated but were hyporesponsive at the single cell level, After 3 days, however, those cells were rapidly deleted, at least partially, through an apoptotic process, Therefore, both thymic and peripheral apoptosis, in addition to T-cell receptor desensitization, contribute to high-dose tolerance.