Hannier S, Tournier M, Bismuth G, Triebel F
Laboratoire d'Immunologie Cellulaire, Institut Gustave-Roussy, Villejuif, France.
J Immunol. 1998 Oct 15;161(8):4058-65.
The lymphocyte activation gene-3 (LAG-3) molecule is a T cell activation Ag closely related to CD4 at the gene and protein levels. We investigated whether LAG-3 itself may down-regulate the immune response by interfering with TCR signaling. The binding of Ab to the LAG-3 molecule followed by cross-linking (XL) inhibits cell proliferation and cytokine secretion in response to CD3XL on activated T cells. LAG-3XL-induced down-regulation is associated with functional unresponsiveness, as well as with high CD25 expression levels and reversion by exogenous IL-2. It is also associated with a down-modulation of CD3/TCR complex expression. At the biochemical level, LAG-3XL inhibits calcium response to CD3 stimulation. This inhibition is observed with different LAG-3- and CD3-specific mAbs on condition that the two receptors are cross-linked together. Finally, the capping of CD3 was shown to induce cocapping of LAG-3 molecules. Together, these results show that CD3/TCR complex-associated LAG-3 molecules can play an active role in negatively regulating the CD3/TCR activation pathway. They ultimately suggest that LAG-3 is an inhibitory receptor in activated T lymphocytes.
淋巴细胞激活基因-3（LAG-3）分子是一种在基因和蛋白质水平上与CD4密切相关的T细胞激活抗原。我们研究了LAG-3本身是否可能通过干扰TCR信号传导来下调免疫反应。抗体与LAG-3分子结合后进行交联（XL）可抑制活化T细胞对CD3XL的细胞增殖和细胞因子分泌。LAG-3XL诱导的下调与功能无反应性有关，也与高CD25表达水平和外源性IL-2的逆转有关。它还与CD3/TCR复合物表达的下调有关。在生化水平上，LAG-3XL抑制对CD3刺激的钙反应。在两个受体交联在一起的条件下，用不同的LAG-3和CD3特异性单克隆抗体可观察到这种抑制作用。最后，CD3的封帽显示可诱导LAG-3分子的共封帽。总之，这些结果表明，与CD3/TCR复合物相关的LAG-3分子可在负向调节CD3/TCR激活途径中发挥积极作用。它们最终表明LAG-3是活化T淋巴细胞中的一种抑制性受体。
