BLIMP1 negatively regulates IL-2 signaling in T cells

IL-2 signaling sustains immune homeostasis by fine-tuning the balance between effector and regulatory T cells. Our genome-wide CRISPR knockout screen using IL-2-dependent cells derived from a patient with Adult T-cell Leukemia (ATL) showed enriched sgRNAs targeting PRDM1 (encoding BLIMP1). BLIMP1 inhibits IL-2 production in T cells; however, its role in IL-2 signaling remains unknown. Here, we show that Prdm1 overexpression decreased IL-2 signaling in CD4+ T cells, while its deletion enhanced IL-2 signaling during influenza infection. Adoptive transfer of Prdm1 CKO Tregs into Rag2-/- mice elevated IL-2 signaling in T-cell induced colitis. Moreover, CRISPR/Cas9-mediated PRDM1 deletion augmented IL-2 signaling in human CD4+ T cells and natural Tregs with BLIMP1 binding to key genes affecting IL-2 signaling. Furthermore, ATL cells from acute patients exhibited increased IL-2 signaling but reduced BLIMP1 induction. Thus, BLIMP1 represses IL-2 signaling in T cells which is critical in orchestrating normal and pathophysiological immune responses. Overall design: CD4+ T cells were purified from frozen PBMCs of healthy donors and acute ATL patients then analyzed using scRNA-seq.白介素2信号通路（IL-2 signaling）通过精准调控效应T细胞与调节性T细胞之间的平衡来维持免疫稳态。本研究利用来自成人T细胞白血病（Adult T-cell Leukemia, ATL）患者的IL-2依赖细胞开展全基因组CRISPR敲除筛选，发现靶向PRDM1（编码BLIMP1）的单引导RNA（sgRNAs）显著富集。BLIMP1可抑制T细胞内IL-2的产生，但其在IL-2信号通路中的作用仍未明确。本研究证实，Prdm1过表达会降低CD4+ T细胞中的IL-2信号通路活性，而敲除Prdm1则可增强流感感染过程中的IL-2信号通路活性。将Prdm1条件性敲除调节性T细胞（Prdm1 CKO Tregs）过继转移至Rag2基因敲除（Rag2-/-）小鼠体内，可提升T细胞诱导性结肠炎模型中的IL-2信号通路活性。此外，经CRISPR/Cas9介导的PRDM1敲除可增强人CD4+ T细胞及天然调节性T细胞（natural Tregs）中的IL-2信号通路活性，且BLIMP1能够结合影响IL-2信号通路的关键基因。进一步研究发现，急性成人T细胞白血病患者的肿瘤细胞中IL-2信号通路活性升高，但BLIMP1的诱导表达水平显著降低。综上，BLIMP1可抑制T细胞内的IL-2信号通路，这在调控正常及病理生理状态下的免疫应答过程中发挥关键作用。 整体实验设计：从健康捐献者与急性成人T细胞白血病患者的冻存外周血单个核细胞（PBMCs）中纯化CD4+ T细胞，随后通过单细胞RNA测序（scRNA-seq）进行分析。