Induction of T cell anergy by low numbers of agonist ligands.
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.
Korb
L C
LC
Department of Pathology, Graduate Program in Immunology, School of Medicine/Johns Hopkins University, Baltimore, MD 21205, USA.
Mirshahidi
S
S
Ramyar
K
K
Sadighi Akha
A A
AA
Sadegh-Nasseri
S
S
D017635:Clonal Anergy / Q000187:drug effects / Q000276:immunology*; D002999:Clone Cells; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology; D015798:HLA-DR1 Antigen / Q000032:analysis; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral / Q000032:analysis / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D046911:Macromolecular Substances; D009975:Orthomyxoviridae / Q000276:immunology; D010446:Peptide Fragments / Q000032:analysis / Q000276:immunology / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000276:immunology
D016207:Cytokines; D015798:HLA-DR1 Antigen; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D008024:Ligands; D046911:Macromolecular Substances; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; C086595:influenza hemagglutinin (306-318); D016572:Cyclosporine