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

gamma delta 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 gamma delta T cell response remain unidentified, and the role of antigen recognition in gamma delta T cell function is contentious. Here, we show that some gamma delta 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 gamma delta 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 gamma delta 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 gamma delta T cells with similar polyspecificity also respond to various immune challenges. This study demonstrates that polyspecificity is a prevalent feature of gamma delta T cell antigen recognition, which enables rapid and robust T cell responses to a wide range of challenges, highlighting a unique function of gamma delta T cells.