Theranostics 2020; 10(18):8051-8060. doi:10.7150/thno.43507

Research Paper

Autophagy-lysosome inhibitor chloroquine prevents CTLA-4 degradation of T cells and attenuates acute rejection in murine skin and heart transplantation

Jikai Cui*, Jizhang Yu*, Heng Xu, Yanqiang Zou, Hao Zhang, Shanshan Chen, Sheng Le, Jing Zhao, Lang Jiang, Jiahong Xia, Jie Wu

Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
*The authors contributed equally to this work.

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Citation:
Cui J, Yu J, Xu H, Zou Y, Zhang H, Chen S, Le S, Zhao J, Jiang L, Xia J, Wu J. Autophagy-lysosome inhibitor chloroquine prevents CTLA-4 degradation of T cells and attenuates acute rejection in murine skin and heart transplantation. Theranostics 2020; 10(18):8051-8060. doi:10.7150/thno.43507. Available from http://www.thno.org/v10p8051.htm

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Abstract

Background: The immune checkpoint cytotoxic T lymphocyte antigen-4 (CTLA-4), induced upon T cell activation but degraded quickly, has been targeted in the clinical therapy of advanced cancers and autoimmune diseases. However, whether inhibiting CTLA-4 degradation ameliorates transplant rejection remains unknown.

Methods: The CTLA-4 expression in activated murine T cells treated with the inhibitors mediating protein degradation was detected by flow cytometry (FCM). CD45.1 mice, which received TEa T cells and underwent heart transplantation, were administrated with the inhibitor. Subsequently, CTLA-4 expression of TEa T cells was analyzed. Murine skin and heart transplantation models were built, then the survival and histopathology of the allografts, and T cell subsets in the spleens of each group were compared.

Results: Chloroquine (CQ) was identified as an inhibitor of CTLA-4 degradation, which augmented both surface and total CTLA-4 expression in T cells. It considerably prolonged the skin and heart allograft survival time and reduced the infiltration of inflammatory cells in allografts. Besides decreasing the frequencies of the CD4+ and CD8+ effector T cells, especially IFN-γ producing T cells, CQ also increased the proportion of regulatory T cells in the spleen. The CTLA-4 blockade abrogated the benefits of CQ on the survival of heart allografts. Moreover, CQ enhanced CTLA-4 expression in activated human T cells and reduced the secretion of IFN-γ in human mixed lymphocyte reaction.

Conclusion: Targeting CTLA-4 degradation provides a novel means to prevent transplant rejection and induce transplant tolerance.

Keywords: Cytotoxic T lymphocyte antigen-4, Chloroquine, Autophagy, T cells, Transplant rejection.