Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.
Blood. 2009 Dec 17;114(26):5299-306. doi: 10.1182/blood-2009-06-228353. Epub 2009 Oct 23.
KLRG1 is an inhibitory receptor expressed on a subset of mature T and NK cells. Recently, E-, N-, and R-cadherin have been identified as ligands for KLRG1. Cadherins are a large family of transmembrane or membrane-associated glycoproteins that were thought to only bind specifically to other cadherins to mediate specific cell-to-cell adhesion in a Ca(2+)-dependent manner. The consequences of cadherin KLRG1 molecular interactions are not well characterized. Here, we report that the first 2 extracellular domains of cadherin are sufficient to initiate a KLRG1-dependent signaling. We also demonstrate that KLRG1 engagement inhibits cadherin-dependent cellular adhesion and influences dendritic cell secretion of inflammatory cytokines, thereby exerting immunosuppressive effects. Consistent with this, engagement of cadherin by KLRG1 molecule induces cadherin tyrosine phosphorylation. Therefore, KLRG1/cadherin interaction leads to the generation of a bidirectional signal in which both KLRG1 and cadherin activate downstream signaling cascades simultaneously. Taken together, our results provide novel insights on how KLRG1 and E-cadherin interactions are integrated to differentially regulate not only KLRG1(+) cells, but also E-cadherin-expressing cells, such as dendritic cells.
KLRG1 是一种表达在成熟 T 细胞和 NK 细胞亚群上的抑制性受体。最近，E、N 和 R 钙黏蛋白已被鉴定为 KLRG1 的配体。钙黏蛋白是一大类跨膜或膜相关糖蛋白，以前认为它们只特异性地与其他钙黏蛋白结合，以依赖 Ca2+的方式介导特定的细胞间黏附。钙黏蛋白与 KLRG1 分子相互作用的后果尚未得到很好的描述。在这里，我们报告钙黏蛋白的前 2 个细胞外结构域足以启动 KLRG1 依赖性信号转导。我们还证明 KLRG1 结合抑制钙黏蛋白依赖性细胞黏附和影响树突状细胞分泌炎症细胞因子，从而发挥免疫抑制作用。与此一致的是，KLRG1 分子与钙黏蛋白的结合诱导钙黏蛋白酪氨酸磷酸化。因此，KLRG1/钙黏蛋白相互作用导致双向信号的产生，其中 KLRG1 和钙黏蛋白同时激活下游信号级联。总之，我们的结果提供了新的见解，即 KLRG1 和 E-钙黏蛋白相互作用如何整合以不同方式调节不仅是 KLRG1(+)细胞，而且还有 E-钙黏蛋白表达细胞，如树突状细胞。
