CD27-expressing xenoantigen-expanded human regulatory T cells are efficient in suppressing xenogeneic immune response
Lu Cao1,3, Xiaoqian Ma1,2,3, Juan Zhang1,2, Min Yang1,2, Zhenhu He2, Cejun Yang1,2, Pengfei Rong2, Wei Wang1,2,3.
1The Institute for Cell Transplantation and Gene Therapy, the Third XiangYa Hospital, Central South University, Changsha, People's Republic of China; 2Department of Radiology, the Third XiangYa Hospital of Central South University, Changsha, People's Republic of China; 3Engineering and Technology Research Center for Xenotransplantation of Human Province, Changsha, People's Republic of China
Background: The clinical application of xenotransplantation often leads to T cell-mediated graft rejection. Immunosuppressive agents including polyclonal regulatory T cells (poly-Tregs) promote global immunosuppression, resulting in serious infection and malignancy in patients. Xenoantigen-expanded Tregs (xeno-Tregs) has become a promising immune therapy strategy that can protect xenografts with less side effects. In this study, we aimed to uncover a more efficient and stabler species of xeno-Tregs.
Methods: We enriched the CD27+ xeno-Tregs by cell sorting and evaluated their suppressive functions and stability in vitro via mixed lymphocyte reaction (MLR), RT-PCR, an inflammatory induction assay and western blotting. A humanized xenotransplanted mouse model was used to evaluate the function of CD27+ xeno-Tregs in vivo.
Results: Our results showed that CD27+ xeno-Tregs expressed higher levels of Foxp3, CTLA-4, and Helios and lower IL-17 than their CD27- counterparts. In addition, CD27+ xeno-Tregs showed significantly enhanced potency in suppressing the proliferation of xenoantigen-specific responder T cells at ratios of 1:4 and 1:16. Under inflammatory conditions, CD27+ xeno-Tregs displayed lower levels of IL-17 and IFN-gamma and less converted to IL17+ cells. Mice received porcine grafts showed normal tissue phenotype and less leukocyte infiltration after the injection of CD27+ xeno-Tregs.
Conclusion: Taken together, these data indicated that CD27+ xeno-Tregs could suppress immune responses in a xenoantigen specific manner, effectively protecting xenografts from tissue damage.
Grant number: 81971721.
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