ZFP148 is a transcriptional checkpoint for effector CD8+ T cell differentiation 3939

Abstract Description In the settings of chronic antigen stimulation, such as chronic viral infection and cancer, antigen-specific CD8+ T cells will differentiate into heterogeneous pool of progenies including progenitor, effector, and exhausted cells. Though genetic and epigenetic programs contribute to the generation of each subset, it remains elusive how their differentiation preferences are dynamically regulated on a higher hierarchy. Here we identified Zinc-Finger Protein 148 (ZFP148) as a transcriptional checkpoint for CD8+ T cell effector differentiation. In both chronic viral infection and cancer, ZFP148-deficient CD8+ T cells accumulated a dramatically increased cytolytic effector cell pool accompanied with diminished progenitor and exhausted cells. Single-cell multiomic analysis identified skewed differentiation of antigen-specific CD8+ T cells into effector lineage in the absence of ZFP148, which was mediated by global regulation of motif accessibility for multiple fate-determining transcription factors such as ZEB2, T-bet, and TCF1. Furthermore, ablation of ZFP148 unleashed cytolytic effector function of T cells and further enhanced their proliferation burst after inhibiting the PD-1 signaling pathway, resulting in potent anti-tumor activity. Thus, CD8+ T cell effector differentiation is subjected to a unique transcriptional repression control by ZFP148, creating a promising opportunity to target ZFP148 for immunotherapy of cancer and infectious diseases. Funding Sources Supported by NIH P01CA278732 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)