The three isoforms of apolipoprotein E (APOE2, APOE3, and APOE4) only differ in two amino acid positions but exert quite different immunomodulatory effects. The underlying mechanism of such APOE isoform dependence remains enigmatic. Here we demonstrate that APOE4, but not APOE2, specifically interacts with the leukocyte immunoglobulin-like receptor B3 (LilrB3). Two discrete immunoglobin-like domains of the LilrB3 extracellular domain (ECD) recognize a positively charged surface patch on the N-terminal domain (NTD) of APOE4. The atomic structure reveals how two APOE4 molecules specifically engage two LilrB3 molecules, bringing their intracellular signaling motifs into close proximity through formation of a hetero-tetrameric complex. Consistent with our biochemical and structural analyses, APOE4, but not APOE2, activates human microglia cells (HMC3) into a pro-inflammatory state in a LilrB3-dependent manner. Together, our study identifies LilrB3 as a putative immune cell surface receptor for APOE4, but not APOE2, and may have implications for understanding the biological functions as well as disease relevance of the APOE isoforms.

载脂蛋白E的三种亚型（APOE2、APOE3和APOE4）仅在两个氨基酸位置上有所不同，但发挥的免疫调节作用却截然不同。这种 APOE 同工型依赖性的潜在机制仍然是个谜。在这里，我们证明 APOE4（而非 APOE2）与白细胞免疫球蛋白样受体 B3 (LilrB3) 特异性相互作用。 LilrB3 胞外域 (ECD) 的两个离散的免疫球蛋白样域识别 APOE4 N 端域 (NTD) 上带正电荷的表面斑块。原子结构揭示了两个 APOE4 分子如何特异性地与两个 LilrB3 分子结合，通过形成异源四聚体复合物，使它们的细胞内信号基序紧密靠近。与我们的生化和结构分析一致，APOE4（而非 APOE2）以 LilrB3 依赖性方式激活人小胶质细胞 (HMC3) 进入促炎状态。总之，我们的研究确定 LilrB3 是 APOE4 的推定免疫细胞表面受体，但不是 APOE2，并且可能对理解 APOE 亚型的生物学功能以及疾病相关性具有影响。