IL-35 Stabilizes Treg Phenotype to Protect Cardiac Allografts in Mice

Huang，Ai1; Liu，Kewei1; Yin，Ziyi2; Liu，Jie2,3; Wei，Hongyan2; Xing，Shijie1,4; Qu，Yue1; Huang，Lei1; Li，Liancheng1; Li，Chang2; Zhang，Lei2; Li，Xiaoshi2; Zheng，Cunni2; Liu，Quan2; Jiang，Ke1

2024

10.1097/TP.0000000000004707

Transplantation   影响因子和分区

0041-1337

Background. Interleukin-35 (IL-35), secreted by regulatory T cells (Treg) and B cells, is immunosuppressive under both physiological and pathological conditions. However, the role of IL-35 in all responses has yet to be investigated. Here, we demonstrate that IL-35 protects allografts by stabilizing the Treg phenotype and suppressing CD8T-cell activation in a mouse heart transplantation model. Methods. The effect of IL-35 on immune cell infiltration in grafts and secondary lymphoid organs was examined using mass cytometry, flow cytometry, and immunofluorescence. Moreover, using quantitative real-time polymerase chain reaction, flow cytometry, and phospho-flow assays, we demonstrated that IL-35 maintains Treg phenotypes to restrain CD8T cells via the gp130/signal transducer and activator of transcription 1 pathway. Results. Mass cytometry analysis of intragraft immune cells showed that IL-35 decreased CD8T-cell infiltration and increased Foxp3 and IL-35 expressions in Treg. In vitro, we demonstrated that IL-35 directly promoted Treg phenotypic and functional stability and its IL-35 secretion, generating a positive feedback loop. However, Treg are required for IL-35 to exert its suppressive effect on CD8T cells in vitro. After depleting Treg in the recipient, IL-35 did not prolong graft survival or decrease CD8T-cell infiltration. Mechanistically, we found that IL-35 sustained Treg stability via the gp130/signal transducer and activator of transcription 1 signaling pathway. Conclusions. Our findings highlight that IL-35 stabilizes the Treg phenotype to ameliorate CD8T-cell infiltration in the allograft, which has never been described in the transplanted immunological milieu.

SCI

英语

其他

CLINICAL MEDICINE

2-s2.0-85179850876

Scopus

1.Department of Thoracic Surgery,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,China
2.Department of Biochemistry,School of Medicine,Southern University of Science and Technology,Shenzhen,China
3.Shenzhen Key Laboratory of Cardiovascular Health and Precision Medicine,Southern University of Science and Technology,Shenzhen,China
4.Key University Laboratory of Metabolism and Health of Guangdong,Southern University of Science and Technology,Shenzhen,China

Huang，Ai,Liu，Kewei,Yin，Ziyi,et al. IL-35 Stabilizes Treg Phenotype to Protect Cardiac Allografts in Mice[J]. Transplantation,2024,108(1):161-174.

Huang，Ai.,Liu，Kewei.,Yin，Ziyi.,Liu，Jie.,Wei，Hongyan.,...&Jiang，Ke.(2024).IL-35 Stabilizes Treg Phenotype to Protect Cardiac Allografts in Mice.Transplantation,108(1),161-174.

Huang，Ai,et al."IL-35 Stabilizes Treg Phenotype to Protect Cardiac Allografts in Mice".Transplantation 108.1(2024):161-174.