Zinc finger protein Zfp335 is required for T cell homeostatic proliferation through regulating Lmnb1

Background: T cell homeostasis is crucial for maintaining T cell population size and upcoming protective immunity in the peripheral organs. However, it remains largely unknown about the intracellular molecules and pathways beyond IL-7R signaling. Zfp335, as a key transcription factor, is involved in the multiple-stage development of thymocytes, and effector and memory T cell differentiation during immune responses. Results: In current study, we found an upregulated expression of ZFP335 in both CD4⁺ and CD8⁺ T cells during peripheral homeostasis. In an adoptive transfer model, Zfp335^−/− T cells failed to undergo homeostatic proliferation without survival defect. Consistently, deletion of Zfp335 impaired T cell proliferation in in vitro culture with IL-7. Furthermore, both RNA-Sequencing and qPCR analysis showed that Zfp335 significantly affected the expression of cell cycle-related genes. Mechanistically, Zfp335 directly binds to the promoter of Lmnb1 gene and regulates its transcription. Overexpression of Lmnb1 significantly rescued the impaired proliferation of Zfp335^−/− T cells. Conclusion: Our results reveal a previously unrecognized role of Zfp335 in maintaining T cell homeostasis within peripheral lymphoid tissues. Specifically, Zfp335 promotes the homeostatic proliferation of naïve T cells by directly modulating the expression of the Lmnb1 gene which ensuring the capacity of immune system.