BOLUS INJECTION OF AQUEOUS ANTIGEN LEADS TO A HIGH-DENSITY OF T-CELL-RECEPTOR LIGAND IN THE SPLEEN, TRANSIENT T-CELL ACTIVATION AND ANERGY INDUCTION

In vivo anergy can be modelled by administration of soluble peptide to T-cell receptor (TCR) transgenic mice specific for the moth cytochrom e c peptide 88-103 (MCCp). Two weeks after initial peptide treatment, T cells were present in normal numbers but were unresponsive to antige n stimulation in vitro. Only bolus injections of peptide, either subcu taneous or intravenous, were effective at inducing tolerance, while sl owly released antigen administered via mini-osmotic pump failed to res ult in anergy. Examination of T cells soon after bolus peptide adminis tration revealed that anergy induction was preceded by a transient hyp eractivation of T cells in vivo. Within 2 hr of peptide treatment, int erleukin-2 was detectable in the plasma of the transgenic mice. Intere stingly, only bolus injections of peptide led to high levels of T-cell activation, while adjuvant emulsified and pump-administered peptide r esulted in very low stimulation in vivo. When the dose of bolus-inject ed peptide used for tolerization was titrated, the extent of anergy in duction directly correlated with the intensity of early T-cell activat ion. Indirect measurements of TCR-ligand density on the surface of ant igen-presenting cells following peptide administration revealed that a queous peptide delivered via bolus injection generated a large number of major histocompatibility complex-peptide complexes, while pump-deli vered and adjuvant-emulsified peptide did not. These data suggest that high levels of TCR ligand are required for in vivo T-cell hyperactiva tion and induction of anergy.