Dissociation of Peripheral T Cell Responses from Thymocyte Negative Selection by Weak Agonists Supports a Spare Receptor Model of T Cell Activation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 99; no. 7; pp. 4520 - 4525
• Main Authors: McNeil, Lisa K., Evavold, Brian D.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.04.2002; National Acad Sciences; The National Academy of Sciences
• Subjects: Agonists; Animals; Biological Sciences; CD4-Positive T-Lymphocytes - immunology; Female; Half lives; Histocompatibility Antigens - metabolism; Ligands; Lymphocyte Activation; Male; Mice; Mice, Transgenic; Models, Immunological; Molecules; Negative selection; Peptides - metabolism; Receptors; Receptors, Antigen, T-Cell - physiology; Splenocytes; T cell antigen receptors; T lymphocytes; Thymocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.072673899

We have focused on stability of the peptide-MHC complex as a determining factor of ligand potency for thymocytes and peripheral CD4+T cell responses. MHC variant peptides that have low affinities and fast dissociation rates are different in that they stimulate proliferation and cytolysis of mature T cells (classifying the variant peptides as weak agonists) but do not induce thymocyte negative selection. The MHC variant weak agonists require significant receptor reserve, because decreasing the level of T cell receptor on mature T cells blocks the proliferative response. These results demonstrate that peripheral T cells are more sensitive to MHC variant ligands by virtue of increased T cell receptor expression; in addition, the data support a T cell model of the spare receptor theory.