Full Text | PDF

Share on tweeters Share on facebook Share on linkedin Share on googleplus

Theranostics 2023; 13(6):1892-1905. doi:10.7150/thno.78078 This issue Cite

Research Paper

HSF1 promotes CD69+ Treg differentiation to inhibit colitis progression

Lei Yu1#, Bingluo Zhou1#, Yiran Zhu1,2, Ling Li1, Yiming Zhong2, Liyuan Zhu1, Hanying Wang2, Hui Chen3, Jinye Xu1, Tianxin Guo4, Lifeng Feng1, Xian Wang2, Zhijian Cai5✉, Jianli Wang6,7✉, Hongchuan Jin1✉

1. Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Center of Zhejiang University, Sir Run Run Shaw hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
2. Department of Medical Oncology, Sir Run Run Shaw hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
3. Department of Pathology, Sir Run Run Shaw hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
4. Department of respiratory medicine, The First People's Hospital of Xiaoshan District, Xiaoshan First Affiliated Hospital of Wenzhou Medical University, Hangzhou, 311200, Zhejiang, China
5. Institute of Immunology, and Department of Orthopedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
6. Institute of Immunology, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
7. Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China
# Equal contribution

✉ Corresponding authors: Prof. Dr. Hongchuan Jin, jinhcedu.cn. Prof. Dr. Zhijian Cai, caizjedu.cn. Prof. Dr. Jianli Wang, jlwangedu.cn

Citation:
Yu L, Zhou B, Zhu Y, Li L, Zhong Y, Zhu L, Wang H, Chen H, Xu J, Guo T, Feng L, Wang X, Cai Z, Wang J, Jin H. HSF1 promotes CD69+ Treg differentiation to inhibit colitis progression. Theranostics 2023; 13(6):1892-1905. doi:10.7150/thno.78078. https://www.thno.org/v13p1892.htm
Other styles

File import instruction

Abstract

Graphic abstract

Regulatory T cells (Tregs) are critical for generating and maintaining peripheral tolerance. Treg-based immunotherapy is valuable for the clinical management of diseases resulting from dysregulation of immune tolerance. However, the lack of potency is a potential limitation of Treg therapy. In addition, CD69 positive-Treg (CD69+ Treg) represent a newly identified subset of Tregs with potent immune suppressive capability.

Methods: Foxp3YFP-CreCD69fl/fl and CD4CreCD69fl/fl mice were generated to determine the relevance of CD69 to Treg. Chromatin Immunoprecipitation Assay (ChIP) and luciferase Assay were performed to detect the regulation of CD69 transcription by heat shock transcription factor 1(HSF1). Gene expression was measured by western blotting and qRT-PCR. The differentiation of naive T cells to CD69+Foxp3+ iTregs was determined by flow cytometry. The immunosuppressive ability of Tregs was analyzed by ELISA and flow cytometry. Colon inflammation in mice was reflected by changes in body weight and colon length, the disease activity index (DAI), and H&E staining of colon tissues.

Results: Induced Tregs (iTregs) from CD4CreCD69fl/fl mice failed to alleviate colitis. The transcription factor HSF1 interacted with the promoter of the CD69 gene to prompt its transcription during Treg differentiation. Genetic and chemical inhibition of HSF1 impaired CD69+ Treg differentiation and promoted the pathogenesis of colitis in mice. In contrast, HSF1 protein stabilized by inhibiting its proteasomal degradation promoted CD69+ Treg differentiation and alleviated colitis in mice. Moreover, adoptive transfer of iTregs with HSF1 stabilization by proteasome inhibitor (PSI) dramatically prevented the development of colitis in mice and was accompanied by decreased production of pro-inflammatory cytokines and reduced accumulation of pro-inflammatory lymphocytes in colitis tissue, whereas Tregs induced in the absence of PSI were less stable and ineffective in suppressing colitis.

Conclusions: HSF1 promotes CD69+ Tregs differentiation by activating the CD69 transcription, which is critical for the immunosuppressive function of Tregs. Stabilization of HSF1 by PSIs results in the efficient generation of Tregs with high potency to treat colitis and probably other autoimmune diseases involving Tregs deficiency.

Keywords: Treg, CD69, HSF1, IBD, proteasome inhibitor

Citation styles

APA
Yu, L., Zhou, B., Zhu, Y., Li, L., Zhong, Y., Zhu, L., Wang, H., Chen, H., Xu, J., Guo, T., Feng, L., Wang, X., Cai, Z., Wang, J., Jin, H. (2023). HSF1 promotes CD69+ Treg differentiation to inhibit colitis progression. Theranostics, 13(6), 1892-1905. https://doi.org/10.7150/thno.78078.

ACS
Yu, L.; Zhou, B.; Zhu, Y.; Li, L.; Zhong, Y.; Zhu, L.; Wang, H.; Chen, H.; Xu, J.; Guo, T.; Feng, L.; Wang, X.; Cai, Z.; Wang, J.; Jin, H. HSF1 promotes CD69+ Treg differentiation to inhibit colitis progression. Theranostics 2023, 13 (6), 1892-1905. DOI: 10.7150/thno.78078.

NLM
Yu L, Zhou B, Zhu Y, Li L, Zhong Y, Zhu L, Wang H, Chen H, Xu J, Guo T, Feng L, Wang X, Cai Z, Wang J, Jin H. HSF1 promotes CD69+ Treg differentiation to inhibit colitis progression. Theranostics 2023; 13(6):1892-1905. doi:10.7150/thno.78078. https://www.thno.org/v13p1892.htm

CSE
Yu L, Zhou B, Zhu Y, Li L, Zhong Y, Zhu L, Wang H, Chen H, Xu J, Guo T, Feng L, Wang X, Cai Z, Wang J, Jin H. 2023. HSF1 promotes CD69+ Treg differentiation to inhibit colitis progression. Theranostics. 13(6):1892-1905.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Popup Image

©2024 Ivyspring International Publisher. Terms of use