Programmed death protein 1 is essential for maintaining the anti-inflammatory function of infiltrating regulatory T cells in a murine spinal cord injury model.

Excessive neuroinflammation exacerbates neuronal impairment after spinal cord injury (SCI). Thymic regulatory T cells (Tregs), macrophages, and microglia play significant roles in the process of post-SCI neuroinflammation. However, the mechanisms by which these cells were modulated in the injured spinal cord remain unclear. In the current research, we applied a murine SCI model to demonstrate the upregulation of programmed death protein 1(PD-1) in infiltrating Tregs and significant expression of programmed death-ligand 1 (PD-L1) on post-SCI macrophages/microglia. Furthermore, through using an inducible shRNA lentivirus system, we showed that Treg-specific PD-1 knockdown impairs the anti-inflammatory function of infiltrating Tregs. PD-1 is crucial for the maintenance of Treg identity and function under the influence of pro-inflammatory macrophages/microglia, and PD-1-deficient Tregs are less competent to inhibit pro-inflammatory macrophages/microglia. Besides, in a murine SCI model using T-and-B-cell-deficient Rag1-/- mice, Treg-specific PD-1 knockdown impairs Treg-mediated neuroprotection in vivo, as evidenced by enlarged lesion area. Taken together, our study revealed that PD-1, which is upregulated on infiltrating Tregs in the subacute phase of SCI, is essential for Tregs to maintain Foxp3 expression and anti-inflammatory activity to counteract the effect of pro-inflammatory macrophages and microglia. Novel therapies targeting Treg PD-1 might benefit SCI treatment.