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

T cell receptors (TCRs) band together to detect minute amounts of antigen, according to Schamel and colleagues on page 493. Their new work shows that TCRs are expressed on the surface of resting T cells either individually or in groups. The grouped TCRs, but not the solitary receptors, were triggered by low dose antigen, suggesting that these receptors must cooperate when antigen is scarce.Whether TCRs exist as solitary entities or whether they group together is a long-standing matter of debate. Previous studies have failed to uncover evidence of grouped (multivalent) TCRs, but this may have resulted from dismantling of the groups as a result of overly harsh purification techniques.

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.