Abstract
Interleukin (IL)-17 plays a key role in immunity. In acute infections, a rapid IL-17 response must be induced without prior antigen exposure, and γδ T cells are the major initial IL-17 producers. In fact, some γδ T cells make IL-17 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 naïve animals. They are known as the natural Tγδ17 (nTγδ17) cells. The rapidity of the nTγδ17 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 nTγδ17 response and/or their presence. To better understand antigen recognition in this rapid IL-17 response, we analyzed the antigen receptor repertoire of IL-1R+/IL-23R+ γδ T cells, a proxy for nTγδ17 cells in naïve 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 γδ T cells and small intestine epithelial γδ lymphocytes expressed diverse TCRs. This remarkable commonality and restricted repertoire of IL-1R+/IL-23R+ γδ T cells underscores the importance of antigen recognition in their establishment/function.
Highlights
Interleukin (IL)-17 is an important cytokine in the inflammatory response
Peritoneal nTγδ17 cells are characterized by their IL-1R expression in rapid response situations [8]; we analyzed IL-1R+ peritoneal γδ T cells from C57/BL6 mice that were intra-peritoneally (i.p.) infected with T. gondii 5 h prior
The T cell receptor (TCR) sequences were determined from a single FACS sorted γδ T cell using a bar-code-enabled high throughput single-cell TCR sequencing strategy
Summary
Interleukin (IL)-17 is an important cytokine in the inflammatory response. It induces chemokines and cytokines that mediate the maturation and release of neutrophils from the bone marrow. Neutrophil recruitment focuses the immune response at the site of infection to reduce pathogen load, and induces the subsequent phases of the inflammatory response, which primes antigen-specific αβ T cell and B cell activation and initiates the resolution program. Both αβ T cells and γδ T cells can make IL-17, αβ T cells producing IL-17 (Th17 cells) require antigen-specific priming and a specific cytokine environment to develop. A rapid IL-17 response must be initiated without prior antigen exposure, and γδ T cells have been identified as the major initial IL-17 producers in infections and after immunization [reviewed in Ref. Some naïve γδ T cells in secondary lymphoid organs undergo antigen-driven activation and differentiation to become IL-17 producers: within 24 h after immunization, antigen-specific γδ T cells in the draining lymph node increase in numbers and show activated phenotypes (e.g., becoming CD44hi and CD62Llo)
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