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

TLDR

T cell antigen recognition paradoxically combines high specificity with low affinity between TCR and MHCp. The authors propose that multivalent TCRs, which can enhance avidity and enable cooperativity, may resolve this paradox. Experimental evidence shows TCRs exist as monovalent and multivalent complexes, with multivalent forms phosphorylating at low antigen doses and both forms at high doses, thereby enabling T cells to detect a broad range of antigen concentrations while retaining high sensitivity.

Abstract

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 (αβγεδεζζ) and multivalent complexes with two or more ligand-binding TCRα/β 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.