The Transcription Factor Zfp335 Promotes Differentiation and Persistence of Memory CD8⁺ T Cells by Regulating TCF-1

Memory CD8⁺ T cells play an essential role in providing effective and lifelong protection against pathogens. Comprehensive transcriptional and epigenetic networks are involved in modulating memory T cell development, but the molecular regulations of CD8⁺ memory T cell formation and long-term persistence remain largely unknown. In this study, we show that zinc finger protein 335 (Zfp335) is indispensable for CD8⁺ T cell memory establishment and maintenance during acute infections. Mice with Zfp335 deletion in CD8⁺ T cells exhibit a significant reduction of memory T cells and memory precursor cells in the contraction phase. Zfp335 deficiency in CD8⁺ T cells resulted in decreased expression of memory featured genes Eomes and IL-2Rβ, leading to a loss of memory identity and an increase of apoptosis in response to IL-7 and IL-15. Mechanistically, Zfp335 directly binds to and regulates TCF-1, known to be critical for memory T cell development. Importantly, overexpression TCF-1 could rescue the defects in the survival of both CD8⁺ memory precursors and memory T cells caused by Zfp335 deficiency. Collectively, our findings reveal that Zfp335 serves as a novel transcriptional factor upstream of TCF-1 in regulating CD8⁺ T cell memory.