Induction of T cell anergy by low numbers of agonist ligands

Engagement of TCR by its ligand, the MHC/peptide complex, causes T cell act ivation. T cells respond positively to stimulation with agonists, and are i nhibited by antagonist MHC/peptide ligands, Failure to induce proper confor mational changes in the TCR or fast TCR/MHC dissociation are the leading mo dels proposed to explain anergy induction hy antagonist ligands, In this st udy, we demonstrate that presentation of between 1 and 10 complexes of agon ist/MHC II by unfixed APC induces T cell anergy that persists up to 7 days and has characteristics similar to anergy induced by antagonist ligand or T CR occupancy without costimulation, Furthermore, anergy-inducing doses of h emagglutinin 306-318 peptide led to the engagement of less than 1000 TCR/CD 3 complexes. Thus, engagement of a subthreshold number of TCR by either a l ow density of agonist/MHC or a 2-3 orders of magnitude higher density of an tagonist/MHC causes anergy, Moreover, we show that anergy induced by low ag onist concentrations is inhibited in the presence of IL-2 or cyclosporin A, suggesting involvement of the calcineurin signaling pathway.