SHIP-1 regulates the differentiation and function of Tregs via inhibiting mTORC1 activity
Cell metabolism is crucial for orchestrating the differentiation and function of regulatory T cells (Tregs). However, the underlying mechanism that coordinates cell metabolism to regulate Treg activity is not completely understood. As a pivotal molecule in lipid metabolism, the role of SHIP-1 in Tregs remains unknown. In this study, we found SHIP-1 Treg KO mice (SHIP-1 specifically deleted in regulatory T cells) had severe autoimmunity with increased Tregs in the thymus and disrupted peripheral T cell homeostasis. Mechanistically, CD4<sup>Cre</sup> Ship-1<sup>flox/flox</sup> mice were found to have increased Treg precursors and SHIP-1 KO Tregs had reduced migration and stability, which caused decreased Tregs in the spleen. Additionally, the suppressive function of Tregs from SHIP-1 KO mice was diminished, along with their promotion of anti-tumor immunity. Interestingly, the PI3K-mTORC1, but not mTORC2, signaling axis was enhanced in SHIP-1 KO Tregs. In vivo treatment of SHIP-1 Treg KO mice with rapamycin rescued the abnormal Treg percentages and peripheral T cell homeostasis, as well as Treg suppressive function. Furthermore, the treatment of wild-type mice with SHIP-1 inhibitor enhanced anti-tumor activity. Our study highlights the SHIP-1-PI3K-mTORC1 axis that regulates Treg differentiation and function, and it is a potential target for cancer treatment.
Authors
- Zuochen Du (ORCID: https://orcid.org/0000-0002-4537-6672)
- Chaohong Liu (ORCID: https://orcid.org/0000-0001-7028-4625)
- Akihiko Yoshimura (ORCID: https://orcid.org/0000-0001-5676-8949)
- Lu Huang (ORCID: https://orcid.org/0000-0002-7820-2177)
- Pei Huang (ORCID: https://orcid.org/0000-0003-2735-7758)
- Lisa S. Westerberg (ORCID: https://orcid.org/0000-0003-2943-2192)
- Xingrong Du (ORCID: https://orcid.org/0000-0001-6427-9600)
- Xiaoyu Sun (ORCID: https://orcid.org/0000-0001-7076-5648)
- Lu Yang (ORCID: https://orcid.org/0000-0003-0595-6311)
- Heather Miller (ORCID: https://orcid.org/0000-0002-4670-2855)
- Xin Tang (ORCID: https://orcid.org/0000-0003-2650-498X)
- Jinzhi Wang (ORCID: https://orcid.org/0009-0005-3842-791X)
- Di Yang (ORCID: https://orcid.org/0009-0009-2779-8589)
- Qian Liu (ORCID: https://orcid.org/0000-0001-5341-1290)
Institutions
- National Institutes of Health (US)
- Zunyi Medical University (CN)
- Keio University (JP)
- Fudan University (CN)
- Karolinska Institutet (SE)
- China International Science and Technology Cooperation (CN)
- National Institute of Allergy and Infectious Diseases (US)
- Children's Hospital of Chongqing Medical University (CN)
- Huazhong University of Science and Technology (CN)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Cellular and Molecular Life Sciences
- Published
- 2024-12-21
- DOI
- https://doi.org/10.1007/s00018-024-05470-2
- Citations
- 3
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.72
Funders
- St. Jude Children's Research Hospital
- National Natural Science Foundation of China