Canonical T cell receptor docking on peptide–MHC is essential for T cell signaling

Making sense of TCR–pMHC topology Most T cells use a T cell receptor (TCR) that recognizes major histocompatibility complex molecules bound to peptides (pMHCs) derived from both self- and foreign antigens. Although there is great variability in the interface because of the diversity of both partners, this interaction displays a canonical docking topology for reasons that remain contested. Zareie et al. tested an assortment of both canonical and reversed-polarity TCRs that were all specific for the same cognate pMHC-I bearing a peptide derived from influenza A virus (IAV) (see the Perspective by Horkova and Stepanek). The authors determined that docking topology was the primary driver of in vivo T cell activation and recruitment when mice were infected with IAV. The canonical topology was required for the formation of a functional signaling complex, suggesting that T cell signaling constraints dictate how TCR and pMHC meet. Science , abe9124, this issue p. eabe9124 ; see also abj2937, p. 1038