Zinc finger protein Zfp335 controls early T cell development and survival through β-selection-dependent and -independent mechanisms
Zinc finger protein Zfp335 controls early T cell development and survival through β-selection-dependent and -independent mechanisms
Abstract T cell development in the thymus undergoes the process of differentiation, selective proliferation and survival from CD4-CD8- double negative (DN) stage to CD4+CD8+ double positive (DP) stage prior to the formation of CD4+ helper and CD8+ cytolytic T cells ready for circulation. Each developmental stage is tightly regulated by sequentially-operating molecular networks, of which only limited numbers of transcription regulators have been deciphered. Here we identified Zfp335 transcription factor as a new player in the regulatory network controlling thymocyte development. We demonstrate that Zfp335 intrinsically controls DN to DP transition, as T cell-specific deficiency in Zfp335 leads to a substantial accumulation of DN3 along with reduction of DP, CD4+ and CD8+ thymocytes. This developmental blockade at DN stage results from the impaired intracellular TCRβ expression as well as increased susceptibility to apoptosis in thymocytes. Transcriptomic and ChIP-seq analyses revealed a direct regulation of transcription factors Bcl6 and Rorc by Zfp335. Importantly, enhanced expression of TCRβ and Bcl6/RorγT restores the developmental defect during DN3 to DN4 transition and improves thymocytes survival, respectively. These findings identify a critical role of Zfp335 in controlling T cell development by maintaining intracellular TCRβ expression-mediated β- selection and independently activating cell survival signaling.
Li Wenhua、Jiao Anjun、Sun Lina、Zhang Cangang、Liu Haiyan、Yang Biao、Wang Xin、Ding Renyi、Yang Xiaofeng、Sun Chenming、Zhang Baojun、Su Yanhong
Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi?ˉan Jiaotong University||Institute of Infection and Immunity, Translational Medicine Institute, Xi?ˉan Jiaotong University Health Science CenterDepartment of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi?ˉan Jiaotong University||Institute of Infection and Immunity, Translational Medicine Institute, Xi?ˉan Jiaotong University Health Science CenterDepartment of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi?ˉan Jiaotong University||Institute of Infection and Immunity, Translational Medicine Institute, Xi?ˉan Jiaotong University Health Science CenterDepartment of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi?ˉan Jiaotong University||Institute of Infection and Immunity, Translational Medicine Institute, Xi?ˉan Jiaotong University Health Science CenterDepartment of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi?ˉan Jiaotong University||Institute of Infection and Immunity, Translational Medicine Institute, Xi?ˉan Jiaotong University Health Science CenterDepartment of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi?ˉan Jiaotong University||Institute of Infection and Immunity, Translational Medicine Institute, Xi?ˉan Jiaotong University Health Science CenterDepartment of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi?ˉan Jiaotong University||Institute of Infection and Immunity, Translational Medicine Institute, Xi?ˉan Jiaotong University Health Science CenterDepartment of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi?ˉan Jiaotong University||Institute of Infection and Immunity, Translational Medicine Institute, Xi?ˉan Jiaotong University Health Science CenterDepartment of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi?ˉan Jiaotong University||Institute of Infection and Immunity, Translational Medicine Institute, Xi?ˉan Jiaotong University Health Science Center||Key Laboratory of Environment and Genes Related to Diseases (Xi?ˉan Jiaotong University), Ministry of Education||Xi?ˉan Key Laboratory of Immune Related DiseasesDepartment of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi?ˉan Jiaotong University||Institute of Infection and Immunity, Translational Medicine Institute, Xi?ˉan Jiaotong University Health Science Center||Xi?ˉan Key Laboratory of Immune Related DiseasesDepartment of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi?ˉan Jiaotong University||Institute of Infection and Immunity, Translational Medicine Institute, Xi?ˉan Jiaotong University Health Science Center||Key Laboratory of Environment and Genes Related to Diseases (Xi?ˉan Jiaotong University), Ministry of Education||Xi?ˉan Key Laboratory of Immune Related DiseasesDepartment of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi?ˉan Jiaotong University||Institute of Infection and Immunity, Translational Medicine Institute, Xi?ˉan Jiaotong University Health Science Center
基础医学分子生物学生理学
thymocyteZfp335differentiationapoptosisβ-selection
Li Wenhua,Jiao Anjun,Sun Lina,Zhang Cangang,Liu Haiyan,Yang Biao,Wang Xin,Ding Renyi,Yang Xiaofeng,Sun Chenming,Zhang Baojun,Su Yanhong.Zinc finger protein Zfp335 controls early T cell development and survival through β-selection-dependent and -independent mechanisms[EB/OL].(2025-03-28)[2025-06-03].https://www.biorxiv.org/content/10.1101/2021.11.21.469458.点此复制
评论