In vivo CRISPR Screening Reveals LBR as a Regulator of CD8 + T Cell Fate Decision

ABSTRACT CD8 + T cells play an important role in anti‐infection and anti‐tumor immunity. Metabolic reprogramming has emerged as a critical regulator of T cell function, yet the roles of specific cholesterol‐associated proteins during T cell fate trajectories remain unclear. Here, using an in vivo CRISPR screen in CD8 + T cells during infection with a customized sgRNA library targeting key cholesterol metabolism‐associated proteins, we successfully identified several candidate targets, including the LBR (Lamin B Receptor). Lbr knockout significantly reduced the proportion and absolute number of short‐lived effector cells (SLECs), severely impairing effector responses, while concomitantly increasing the memory precursor population upon LCMV infection. Furthermore, transcriptomic analysis revealed that Lbr depletion markedly altered signaling pathways governing effector T cell differentiation. These findings reveal the role of LBR in modulating effector and memory T cell differentiation, suggesting it as a potential target for metabolic reprogramming to enhance T cell‐based immunotherapies.