Theranostics 2020; 10(9):4217-4232. doi:10.7150/thno.40663 This issue Cite

Research Paper

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

Cai Liang1*, Kevin Y. Yang1*, Vicken W. Chan1, Xisheng Li1, Tiffany H.W. Fung2, Yalan Wu3,4, Xiao Yu Tian3,4, Yu Huang3,4,5, Ling Qin5,6, James Y.W. Lau7, Kathy O. Lui1,5✉

1. Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.
2. Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
3. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
4. Institute of Vascular Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
5. Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.
6. Department of Orthopaedics and Traumatology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
7. Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
*These authors contributed equally to this work

Citation:
Liang C, Yang KY, Chan VW, Li X, Fung THW, Wu Y, Tian XY, Huang Y, Qin L, Lau JYW, Lui KO. CD8+ T-cell plasticity regulates vascular regeneration in type-2 diabetes. Theranostics 2020; 10(9):4217-4232. doi:10.7150/thno.40663. https://www.thno.org/v10p4217.htm
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Abstract

Graphic abstract

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 Leprdb/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.

Keywords: CD8+ T-cells, T-cell plasticity, CD8 checkpoint blockade, vascular regeneration, type-2 diabetes, single cell RNA-seq


Citation styles

APA
Liang, C., Yang, K.Y., Chan, V.W., Li, X., Fung, T.H.W., Wu, Y., Tian, X.Y., Huang, Y., Qin, L., Lau, J.Y.W., Lui, K.O. (2020). CD8+ T-cell plasticity regulates vascular regeneration in type-2 diabetes. Theranostics, 10(9), 4217-4232. https://doi.org/10.7150/thno.40663.

ACS
Liang, C.; Yang, K.Y.; Chan, V.W.; Li, X.; Fung, T.H.W.; Wu, Y.; Tian, X.Y.; Huang, Y.; Qin, L.; Lau, J.Y.W.; Lui, K.O. CD8+ T-cell plasticity regulates vascular regeneration in type-2 diabetes. Theranostics 2020, 10 (9), 4217-4232. DOI: 10.7150/thno.40663.

NLM
Liang C, Yang KY, Chan VW, Li X, Fung THW, Wu Y, Tian XY, Huang Y, Qin L, Lau JYW, Lui KO. CD8+ T-cell plasticity regulates vascular regeneration in type-2 diabetes. Theranostics 2020; 10(9):4217-4232. doi:10.7150/thno.40663. https://www.thno.org/v10p4217.htm

CSE
Liang C, Yang KY, Chan VW, Li X, Fung THW, Wu Y, Tian XY, Huang Y, Qin L, Lau JYW, Lui KO. 2020. CD8+ T-cell plasticity regulates vascular regeneration in type-2 diabetes. Theranostics. 10(9):4217-4232.

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