CD4+CD25- T-Cell-Secreted IFN-γ Promotes Corneal Nerve Degeneration in Diabetic Mice

This study aimed to explore the relationship between corneal nerve degeneration and elevated dendritic cells (DCs) in diabetic keratopathy.

Corneas from diabetic and healthy mice were analyzed using single-cell RNA sequencing. Corneal nerve density and DC and T-cell infiltration were quantified through whole-mount corneal staining. Freshly isolated mouse trigeminal ganglion (TG) neurons were co-cultured with immature DCs, mature DCs, activated CD8+ T cells, and CD4+CD25- T cells. TG neurite outgrowth was assessed to identify potential effector cells driving corneal nerve degeneration. In addition, interferon-gamma (IFN-γ) and blocking antibodies were used to evaluate their effects on TG neurite outgrowth and corneal nerve degeneration in mice.

Compared with age-matched healthy mice, diabetic mice exhibited a significant reduction in corneal nerve density and sensitivity, along with increased infiltration of DCs, CD4+ T cells, and CD8+ T cells. In vitro co-culture experiments revealed that CD4+CD25- T cells, rather than DCs and CD8+ T cells, significantly inhibited TG neurite outgrowth. Among cytokines, elevated IFN-γ in diabetic corneas impaired TG neurite outgrowth and induced corneal nerve degeneration, whereas IL-4 and IL-17 had no such effect. Blocking IFN-γ alleviated CD4+CD25- T-cell-induced inhibition of TG neurite outgrowth and corneal nerve degeneration in diabetic mice.

CD4+CD25- T cells, but not DCs or CD8+ T cells, contribute to corneal nerve degeneration in diabetic mice, a process partially mediated by IFN-γ.