Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response

• Published in: The Journal of experimental medicine Vol. 202; no. 4; pp. 493 - 503
• Main Authors: Schamel, Wolfgang W A, Arechaga, Ignacio, Risueño, Ruth M, van Santen, Hisse M, Cabezas, Pilar, Risco, Cristina, Valpuesta, José M, Alarcón, Balbino
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 15.08.2005
• Subjects: Animals; Antigen Presentation - immunology; Antigens - immunology; Cell Line; Cell Proliferation; Dose-Response Relationship, Immunologic; Humans; Hybridomas; Lymphocyte Activation - immunology; Major Histocompatibility Complex - immunology; Peptides - immunology; Phosphorylation; Rabbits; Receptors, Antigen, T-Cell, alpha-beta - immunology; T-Lymphocytes - immunology; T-Lymphocytes - ultrastructure
• ISSN: 0022-1007; 1540-9538; 1892-1007
• DOI: 10.1084/jem.20042155

A long-standing paradox in the study of T cell antigen recognition is that of the high specificity-low affinity T cell receptor (TCR)-major histocompatibility complex peptide (MHCp) interaction. The existence of multivalent TCRs could resolve this paradox because they can simultaneously improve the avidity observed for monovalent interactions and allow for cooperative effects. We have studied the stoichiometry of the TCR by Blue Native-polyacrylamide gel electrophoresis and found that the TCR exists as a mixture of monovalent (alphabetagammaepsilondeltaepsilonzetazeta) and multivalent complexes with two or more ligand-binding TCRalpha/beta subunits. The coexistence of monovalent and multivalent complexes was confirmed by electron microscopy after label fracture of intact T cells, thus ruling out any possible artifact caused by detergent solubilization. We found that although only the multivalent complexes become phosphorylated at low antigen doses, both multivalent and monovalent TCRs are phosphorylated at higher doses. Thus, the multivalent TCRs could be responsible for sensing low concentrations of antigen, whereas the monovalent TCRs could be responsible for dose-response effects at high concentrations, conditions in which the multivalent TCRs are saturated. Thus, besides resolving TCR stoichiometry, these data can explain how T cells respond to a wide range of MHCp concentrations while maintaining high sensitivity.