A highly focused antigen receptor repertoire characterizes gamma delta T cells that are poised to make IL-17 rapidly in naive animals

Interleukin (IL)-17 plays a key role in immunity. In acute infections, a rapid 11517 response must be induced without prior antigen exposure, and y delta T cells are the major initial IL-17 producers. In fact, some y delta T cells make 11517 within hours after an immune challenge. These cells appear to acquire the ability to respond to IL-1 and IL-23 and to make IL-17 naturally in naive animals. They are known as the natural Ty delta 17 (nT gamma delta 17) cells.The rapidity of the nT gamma delta 17 response, and the apparent lack of explicit T cell receptor (TCR) engagement for its induction have led to the view that this is a cytokine (IL-1, IL-23)-mediated response. However, pharmacological inhibition or genetic defects in TCR signaling drastically reduce the nT gamma delta 17 response and/or their presence. To better understand antigen recognition in this rapid 11517 response, we analyzed the antigen receptor repertoire of IL-R+/IL-23R(+) y delta T cells, a proxy for nT delta 17 cells in naive animals directly ex vivo, using a barcode-enabled high throughput single-cell TCR sequence analysis. We found that regardless of their anatomical origin, these cells have a highly focused TCR repertoire. In particular, the TCR sequences have limited V gene combinations, little or no junctional diversity and much reduced or no N region diversity. In contrast, IL-23R(-) cells at mucosal sites similar to most of the splenic y delta T cells and small intestine epithelial y delta lymphocytes expressed diverse TCRs. This remarkable commonality and restricted repertoire of IL-1R(+)/IL-23R(+) y delta T cells underscores the importance of antigen recognition in their establishment/function.