The Journal of Experimental Medicine
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Published online 8 August 2005 doi:10.1084/jem.20042155
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 4, 493-503
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ARTICLE

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

Wolfgang W.A. Schamel1,3, Ignacio Arechaga2, Ruth M. Risueño1, Hisse M. van Santen1, Pilar Cabezas2, Cristina Risco2, José M. Valpuesta2, and Balbino Alarcón1

1 Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas–Universidad Autónoma de Madrid, Madrid 28049, Spain
2 Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas–Universidad Autónoma de Madrid, Madrid 28049, Spain
3 Max-Planck-Institut für Immunbiologie, 79108 Freiburg, Germany

CORRESPONDENCE Wolfgang W.A. Schamel: schamel{at}immunbio.mpg.de OR Balbino Alarcón: balarcon{at}cbm.uam.es

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 ({alpha}ß{gamma}{varepsilon}{delta}{varepsilon}{zeta}{zeta}) and multivalent complexes with two or more ligand-binding TCR{alpha}/ß 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.

Abbreviations used: BCR, B cell antigen receptor; BN, Blue Native; Jk, Jurkat; MßCD, methyl-ß-cyclodextrin; NIP, iodo-NP; NP, nitro-hydroxy-phenylacetate; MHCp, MHC peptide; PCC, pigeon cytochrome c; sc, single chain.


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