1. Induction of T Cell Anergy by Low Numbers of Agonist Ligands
- Author
-
Korb, L. C., Mirshahidi, S., Ramyar, K., Sadighi Akha, A. A., and Scheherazade Sadegh-Nasseri
- Subjects
Clonal Anergy ,Time Factors ,Macromolecular Substances ,T-Lymphocytes ,Immunology ,Dose-Response Relationship, Immunologic ,HLA-DR1 Antigen ,Receptors, Antigen, T-Cell ,Down-Regulation ,Hemagglutinins, Viral ,Hemagglutinin Glycoproteins, Influenza Virus ,Receptors, Interleukin-2 ,Ligands ,Lymphocyte Activation ,Orthomyxoviridae ,Peptide Fragments ,Clone Cells ,Up-Regulation ,Cyclosporine ,Cytokines ,Humans ,Interleukin-2 ,Immunology and Allergy ,Immunosuppressive Agents - Abstract
Engagement of TCR by its ligand, the MHC/peptide complex, causes T cell activation. T cells respond positively to stimulation with agonists, and are inhibited by antagonist MHC/peptide ligands. Failure to induce proper conformational changes in the TCR or fast TCR/MHC dissociation are the leading models proposed to explain anergy induction by antagonist ligands. In this study, we demonstrate that presentation of between 1 and 10 complexes of agonist/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 TCR occupancy without costimulation. Furthermore, anergy-inducing doses of hemagglutinin 306–318 peptide led to the engagement of less than 1000 TCR/CD3 complexes. Thus, engagement of a subthreshold number of TCR by either a low density of agonist/MHC or a 2–3 orders of magnitude higher density of antagonist/MHC causes anergy. Moreover, we show that anergy induced by low agonist concentrations is inhibited in the presence of IL-2 or cyclosporin A, suggesting involvement of the calcineurin signaling pathway.
- Published
- 1999