Abstract

Gamma/delta ({gamma}{delta}) T cells are unconventional adaptive lymphocytes that recognize structurally diverse ligands via somatically-recombined antigen receptors ({gamma}{delta} TCRs). The molecular mechanism by which ligand recognition initiates {gamma}{delta} TCR signaling, a process known as TCR triggering, remains elusive. Unlike {beta} TCRs, {gamma}{delta} TCRs are not mechanosensitive, and do not require coreceptors or typical binding-induced conformational changes for triggering. Here, we show that {gamma}{delta} TCR triggering by nonclassical MHC class Ib antigens, a major class of ligands recognized by {gamma}{delta} T cells, requires steric segregation of the large cell-surface phosphatases CD45 and CD148 from engaged TCRs at synaptic close contact zones. Increasing access of these inhibitory phosphatases to sites of TCR engagement, by elongating MHC class Ib ligands or truncating CD45/148 ectodomains, abrogates TCR triggering and T cell activation. Our results identify a critical step in {gamma}{delta} TCR triggering and provide insight into the core triggering mechanism of endogenous and synthetic tyrosine-phosphorylated immunoreceptors.