Downregulation of regulatory T cell function in patients with delayed fracture healing

Bone fracture healing is a multistage regenerative process that requires the collaboration of various cell types, with approximately 5%-10% of fractures not healing properly. Accumulating evidence suggests that dysregulations in the immune system are associated with defective healing. In a cohort of 30 bone fracture patients between 50 and 62 years of age, 8 patients displayed delayed healing. Compared to the 22 normal healing patients, these 8 delayed healing patients presented significantly lower frequencies of CD4⁺ CD25^hi Foxp3⁺ canonical regulatory T cells immediately following bone fracture and early on during the healing process. The CD4⁺ CD25^+/hi T cells from delayed healing patients also presented reduced capacity to express transforming growth factor beta (TGF-β), and presented reduced surface expression levels of inhibitory molecules, including CTLA-4 and Lag-3, compared to CD4⁺ CD25^+/hi T cells from normal healing patients. Moreover, CD4⁺ CD25^+/hi T cells from delayed healing patients were less potent in the suppression of CD4⁺ CD25^- autologous conventional T cell proliferation, and presented reduced expansion capacity in response to interleukin (IL)-2 stimulation. Overall, our results demonstrated multiple reductions in regulatory T cell function in delayed healing patients that could produce long-lasting consequences in the bone fracture healing process.