Regunathan Jeyarani, Chen Yuhong, Wang Demin, Malarkannan Subramaniam
Blood Research Institute, Blood Center of Southeastern Wisconsin, Milwaukee 53226, USA.
Blood. 2005 Jan 1;105(1):233-40. doi: 10.1182/blood-2004-03-1075. Epub 2004 Aug 24.
Interaction of the activating ligand H60 with NKG2D receptor constitutes a major stimulatory pathway for natural killer (NK) cells. The influence of inhibitory Ly49 receptors on NKG2D-mediated activation is not clearly understood. Here we show that the magnitude of NKG2D-mediated cytotoxicity is directly proportional to both the levels of H60 and the nature of major histocompatibility complex (MHC) class I molecules expressed on the target cells. The expression levels of H60 on the target cells determined the extent to which the inhibition by Ly49C/I receptors can be overridden. In contrast, even a higher expression of H60 molecule on the target cells failed to overcome the inhibition mediated by Ly49A/G receptors. Also, the level of interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) generated by NK cells through anti-NKG2D monoclonal antibody (mAb)-mediated activation is significantly reduced by the presence of immobilized anti-Ly49A/G mAbs. Thus, NKG2D-mediated cytotoxicity and cytokine secretion results from the fine balance between activating and inhibitory receptors, thereby defining the NK cell-mediated immune responses.
激活配体H60与NKG2D受体的相互作用构成了自然杀伤（NK）细胞的主要刺激途径。抑制性Ly49受体对NKG2D介导的激活的影响尚不清楚。在此我们表明，NKG2D介导的细胞毒性强度与H60水平以及靶细胞上表达的主要组织相容性复合体（MHC）I类分子的性质直接相关。靶细胞上H60的表达水平决定了Ly49C/I受体的抑制作用能够被克服的程度。相反，即使靶细胞上H60分子表达水平更高，也无法克服Ly49A/G受体介导的抑制作用。此外，固定化的抗Ly49A/G单克隆抗体（mAb）的存在会显著降低NK细胞通过抗NKG2D单克隆抗体（mAb）介导的激活产生的干扰素-γ（IFN-γ）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）水平。因此，NKG2D介导的细胞毒性和细胞因子分泌源于激活受体和抑制受体之间的精细平衡，从而决定了NK细胞介导的免疫反应。
