CD8⁺ T-cell plasticity regulates vascular regeneration in type-2 diabetes

In this study, we observe that the ischemic tissues of type-2 diabetic (T2D) patients and mice have significantly more CD8⁺ T-cells than that of their normoglycemic counterparts, respectively. However, the role of CD8⁺ T-cells in the pathogenesis of diabetic vascular complication has been less studied. Methods: We employed loss-of-function studies in mouse models using the non-lytic anti-CD8 antibody that blocks tissue infiltration of CD8⁺ T-cells into the injured tissue. We also performed genome-wide, single-cell RNA-sequencing of CD8⁺ T-cells to uncover their role in the pathogenesis of diabetic vascular diseases. Results: The vascular density is negatively correlated with the number of CD8⁺ T-cells in the ischemic tissues of patients and mice after injury. CD8⁺ T-cells or their supernatant can directly impair human and murine angiogenesis. Compared to normoglycemic mice that can regenerate their blood vessels after injury, T2D mice fail in this regeneration. Treatment with the CD8 checkpoint blocking antibody increases the proliferation and function of endothelial cells in both Lepr^db/db mice and diet-induced diabetic Cdh5-Cre;Rosa-YFP lineage-tracing mice after ischemic injury. Furthermore, single-cell transcriptomic profiling reveals that CD8⁺ T-cells of T2D mice showed a de novo cell fate change from the angiogenic, tissue-resident memory cells towards the effector and effector memory cells after injury. Functional revascularization by CD8 checkpoint blockade is mediated through unleashing such a poised lineage commitment of CD8⁺ T-cells from T2D mice. Conclusion: Our results reveal that CD8⁺ T-cell plasticity regulates vascular regeneration; and give clinically relevant insights into the potential development of immunotherapy targeting vascular diseases associated with obesity and diabetes.