Callus [gamma][delta] T cells and microbe-induced intestinal Th17 cells improve fracture healing in mice

• Published in: The Journal of clinical investigation 2023-04, Vol.133 (8)
• Main Authors: Dar, Hamid Y, Perrien, Daniel S, Pal, Subhashis, Stoica, Andreea, Uppuganti, Sasidhar, Nyman, Jeffry S, Jones, Rheinallt M, Weitzmann, M. Neale, Pacifici, Roberto
• Format: Article
• Language: English
• Subjects: Care and treatment; Fractures; Health aspects; Inflammation; Metronidazole; Microbiota (Symbiotic organisms); Neomycin; Patient outcomes; Permeability; T cells
• ISSN: 0021-9738
• DOI: 10.1172/JCI166577

IL-17A (IL-17), a driver of the inflammatory phase of fracture repair, is produced locally by several cell lineages including [gamma][delta] T cells and Th17 cells. However, the origin of these T cells and their relevance for fracture repair are unknown. Here, we show that fractures rapidly expanded callus [gamma][delta] T cells, which led to increased gut permeability by promoting systemic inflammation. When the microbiota contained the Th17 cell-inducing taxon segmented filamentous bacteria (SFB), activation of [gamma][delta] T cells was followed by expansion of intestinal Th17 cells, their migration to the callus, and improved fracture repair. Mechanistically, fractures increased the S1P receptor 1-mediated (S1PR1-mediated) egress of Th17 cells from the intestine and enhanced their homing to the callus through a CCL20-mediated mechanism. Fracture repair was impaired by deletion of [gamma][delta] T cells, depletion of the microbiome by antibiotics (Abx), blockade of Th17 cell egress from the gut, or Ab neutralization of Th17 cell influx into the callus. These findings demonstrate the relevance of the microbiome and T cell trafficking for fracture repair. Modifications of microbiome composition via Th17 cell-inducing bacteriotherapy and avoidance of broad-spectrum Abx may represent novel therapeutic strategies to optimize fracture healing.