Regulation of natural killer cell activity

自然杀伤(NK)细胞是除B细胞和T细胞外的第三种淋巴细胞亚型。NK细胞在抵御病毒和其他细胞内病原体方面具有重要的免疫功能。与B细胞和T细胞不同，NK细胞不表现出对抗原的特异性，它们之所以得名，是因为它们有在没有抗原刺激的情况下杀死细胞的倾向。NK细胞上识别主要组织相容性I类分子的抑制性受体可以阻止对正常健康细胞的杀伤。令人惊讶的是，人们对激活NK细胞细胞毒性反应的受体知之甚少。这个项目的一个主要目标是确定NK细胞激活的分子基础，并表征涉及的受体。此外，还建立了小鼠体内模型，以确定在各种病原体作用下如何控制NK细胞和肥大细胞的激活和抑制。gp49B受体在NK细胞和肥大细胞中都具有抑制活性。已经产生了gp49B基因缺陷的小鼠。这种gp49缺陷的小鼠已经与同源品系的小鼠杂交了几代，以获得相当纯粹的遗传背景。Gp49B基因缺陷小鼠NK细胞发育正常，体外显示正常的细胞毒活性。同样，gp49B基因缺陷小鼠的肥大细胞发育正常，体外也显示出正常的脱颗粒活性。Gp49B缺失小鼠的健康状况使它们非常适合于测试gp49B在感染期间控制免疫反应的作用，特别是那些已知能引起NK或肥大细胞反应的免疫反应。

Natural killer (NK) cells are a third subtype of lymphocytes besides B and T cells. NK cells provide an important immune function in the defense against viruses and other intracellular pathogens. Unlike B and T cells, NK cells do not exhibit specificity for antigen and they acquired their name because of their propensity to kill cells without prior stimulation by antigen. The killing of normal healthy cells is prevented by inhibitory receptors on NK cells that recognize major histocompatibility class I molecules. Surprisingly little is known about receptors that activate the cytotoxic response of NK cells. A major goal of this project is to define the molecular basis of NK cell activation and to characterize the receptors involved. In addition, an in vivo model in mice has been developed to determine how activation and inhibition of NK cells and mast cells are controlled during exposure to various pathogens.The gp49B receptor has an inhibitory activity in both NK cells and mast cells. Mice deficient in the gp49B gene have been generated. Such gp49-deficient mice have been crossed for several generations with a congenic strain of mice in order to obtain a fairly pure genetic background. NK cells developed normally in gp49B-deficient mice and displayed normal cytotoxic activity in vitro. Likewise, mast cells developed normally in gp49B-deficient mice and displayed normal degranulation activity in vitro. The healthy status of gp49B-null mice makes them very suitable for testing the role of gp49B in controlling immune responses during infections, in particular those known to elicit NK or mast cell responses.