Lee Kyung-Mi, McNerney Megan E, Stepp Susan E, Mathew Porunelloor A, Schatzle John D, Bennett Michael, Kumar Vinay
Department of Biochemistry, Korea University College of Medicine, Sungbuk-Gu, Anam-Dong, Seoul 136-705, Korea.
J Exp Med. 2004 May 3;199(9):1245-54. doi: 10.1084/jem.20031989.
Natural killer (NK) cells are critical in the immune response to tumor cells, virally infected cells, and bone marrow allografts. 2B4 (CD244) is expressed on all NK cells and the ligand for 2B4, CD48, is expressed on hematopoietic cells. Cross-linking 2B4 on NK cells with anti-2B4 monoclonal antibody leads to NK cell activation in vitro. Therefore, 2B4 is considered to be an activating receptor. Surprisingly, we have found, using antibody-blocking and 2B4-deficient NK cells, that NK lysis of CD48(+) tumor and allogeneic targets is inhibited by 2B4 ligation. Interferon gamma production by NK cells is also inhibited. Using a peritoneal tumor clearance assay, it was found that 2B4(-/-) mice have increased clearance of CD48(+) tumor cells in vivo. Retroviral transduction of 2B4 was sufficient to restore inhibition in 2B4(-/-) primary NK cells. It was found that although mature NK cells express SH2D1A, in vitro-derived NK cells do not. However, both populations are inhibited by 2B4 ligation. This indicates that 2B4 inhibitory signaling occurs regardless of the presence of SH2D1A. These findings reveal a novel role for 2B4 as a non-major histocompatibility complex binding negative regulator of NK cells.
自然杀伤（NK）细胞在对肿瘤细胞、病毒感染细胞和骨髓同种异体移植物的免疫反应中起关键作用。2B4（CD244）在所有NK细胞上表达，而2B4的配体CD48在造血细胞上表达。用抗2B4单克隆抗体交联NK细胞上的2B4可导致体外NK细胞活化。因此，2B4被认为是一种激活受体。令人惊讶的是，我们使用抗体阻断和2B4缺陷型NK细胞发现，2B4连接会抑制NK细胞对CD48(+)肿瘤细胞和同种异体靶标的杀伤作用。NK细胞产生的干扰素γ也受到抑制。通过腹膜肿瘤清除试验发现，2B4(-/-)小鼠体内CD48(+)肿瘤细胞的清除率增加。2B4的逆转录病毒转导足以恢复2B4(-/-)原代NK细胞中的抑制作用。研究发现，虽然成熟NK细胞表达SH2D1A，但体外培养的NK细胞不表达。然而，这两种细胞群体都受到2B4连接的抑制。这表明无论SH2D1A是否存在，2B4抑制信号都会发生。这些发现揭示了2B4作为NK细胞的一种非主要组织相容性复合体结合负调节因子的新作用。
