?d T cell antigen receptor polyspecificity enables T cell responses to a broad range of immune challenges

?d T cells are essential for immune defense and modulating physiological processes. While they have the potential to recognize large numbers of antigens through somatic gene rearrangement, the antigens which trigger most ?d T cell response remain unidentified, and the role of antigen recognition in ?d T cell function is contentious. Here, we show that some ?d T cell receptors (TCRs) exhibit polyspecificity, recognizing multiple ligands of diverse molecular nature. These ligands include haptens, metabolites, neurotransmitters, posttranslational modifications, as well as peptides and proteins of microbial and host origin. Polyspecific ?d T cells are enriched among activated cells in naive mice and the responding population in infection. They express diverse TCR sequences, have different functional potentials, and include the innate-like ?d T cells, such as the major IL-17 responders in various pathological/physiological conditions. We demonstrate that encountering their antigenic microbiome metabolite maintains their homeostasis and functional response, indicating that their ability to recognize multiple ligands is essential for their function. Human ?d T cells with similar polyspecificity also respond to various immune challenges. This study demonstrates that polyspecificity is a prevalent feature of ?d T cell antigen recognition, which enables rapid and robust T cell responses to a wide range of challenges, highlighting a unique function of ?d T cells. Overall design: To better understand the functional potential of poly-specific ?d T cells, Cy3+HA+ ?d T cells were sorted from the spleen of naïve mice and subjected to single-cell RNA-seq analysis by Smart-seq2.