Korb L C, Mirshahidi S, Ramyar K, Sadighi Akha A A, Sadegh-Nasseri S
Department of Pathology, Graduate Program in Immunology, School of Medicine/Johns Hopkins University, Baltimore, MD 21205, USA.
J Immunol. 1999 Jun 1;162(11):6401-9.
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.
TCR与其配体MHC/肽复合物的结合会导致T细胞活化。T细胞对激动剂刺激产生阳性反应，并被拮抗剂MHC/肽配体抑制。未能在TCR中诱导适当的构象变化或TCR/MHC快速解离是提出的用于解释拮抗剂配体诱导无反应性的主要模型。在本研究中，我们证明未固定的抗原呈递细胞（APC）呈递1至10个激动剂/MHC II复合物会诱导T细胞无反应性，这种无反应性可持续长达7天，并且具有与拮抗剂配体或无共刺激的TCR占据诱导的无反应性相似的特征。此外，诱导无反应性剂量的血凝素306 - 318肽导致少于1000个TCR/CD3复合物的结合。因此，低密度的激动剂/MHC或密度高2 - 3个数量级的拮抗剂/MHC与低于阈值数量的TCR结合都会导致无反应性。此外，我们表明在存在白细胞介素-2或环孢素A的情况下，低浓度激动剂诱导的无反应性受到抑制，这表明钙调神经磷酸酶信号通路参与其中。
