T cell receptors are expressed either individually (red arrows) or as multivalent groups (black arrows). Only grouped TCRs respond to low-dose antigen.

In the new study, Schamel et al. gently coaxed the TCRs from the cell membrane using a mild detergent, allowing the receptors to retain both their native conformation and any associations with neighboring membrane proteins. They discovered that up to 50% of TCRs expressed by naive T cells associated with other TCRs and formed linear multivalent chains on the cell surface.

Only the multivalent TCRs became phosphorylated in response to low doses of antigen, which might explain how T cells can detect and respond to rare antigenic peptide–MHC complexes amidst a sea of self peptide–MHC pairs. The authors suggest that preexisting clusters of TCRs may allow the responding TCR to facilitate phosphorylation of its neighbor, triggering a chain reaction and making the most of an otherwise weak signal. The research teams are now looking for multivalent TCRs on activated and memory T cells. They suspect that a higher proportion of multivalent TCRs on these cells might in part explain these cells' increased responsiveness to antigen.