ANALYSIS OF HUMAN NK FUNCTION

主要组织相容性复合体(MHC)在 调节免疫反应，但MHC分子也可能 在各种细胞功能中有更广泛的作用。 MHC分子与细胞表面分子相关，参与 细胞生长，也有许多共同的物理特征 受体分子。因此，MHC分子很可能 也有受体功能。 本提案侧重于MHC的两个附加功能 我们最近描述的分子：调节 人自然杀伤(NK)细胞的杀细胞活性及其在 人T、B淋巴细胞的活化与增殖 和NK细胞。这个项目的主要目标是确定 MHC细胞表面分子影响两者的机制 细胞溶解活性和淋巴细胞的生长和激活。 针对人类白细胞抗原I类和人类白细胞抗原I类的特异性单抗 产生了影响裂解活性的II类分子 人NK细胞克隆株(NK3.3)。人类白细胞抗原I类- 增强裂解作用的特异性单抗(单抗131)已被 其特征是一种独特的抗人类白细胞抗原-A位点特异性单抗。在……里面 相比之下，抗人类白细胞抗原-B位点特异性单抗(4E)可以抑制杀伤， 提示人类白细胞抗原I类基因座对NK功能的影响。 类似地，抗人类白细胞抗原-A和抗人类白细胞抗原-B位点特异性单抗 对T和B淋巴细胞的激活有不同的影响 由多种有丝分裂原引起。人类白细胞抗原-A的这种功能差异 和B基因座编码的基因产品以前没有 描述。因此，这些单抗是了解 MHC分子在淋巴细胞功能中的作用。在工作中 假设是：1)MHC分子在功能上与 NK细胞膜、T细胞膜和B细胞膜上的重要受体 细胞；2)人类白细胞抗原A、B位点基因产物形成 不同的联想导致不同的功能效应 抗体是针对它们的。我们将检验这一假设 通过：1)检查MHC I A类的潜在物理关联 和B位点编码的分子与其他功能重要的分子 NK、T和B细胞上的分子，2)差异循环研究 和这些细胞中MHC分子的磷酸化，以及3) 研究早期代谢事件和基因表达的变化 与NK、T和B细胞的激活或溶解活性有关 抗人类白细胞抗原和B位点特异性抗体的存在和缺失 单抗。这些研究将提供有关这一角色的进一步信息 MHC的细胞功能，包括生长，并提供 更深入地了解溶血素的作用机制和调节 功能和细胞增殖。

The major histocompatibility complex (MHC) plays a key role in regulating the immune response, but MHC molecules may also have a more generalized role in a variety of cellular functions. MHC molecules associate with cell surface molecules involved in cell growth and also share many physical characteristics with receptor molecules. It is thus likely that MHC molecules may have receptor functions as well. This proposal focuses on two additional functions of MHC molecules that we recently described: the regulation of the cytolytic activity of human natural killer (NK) cells, and a role in the activation and proliferation of human T and B lymphocytes and NK cells. The major goal of this project is to determine the mechanism by which MHC cell surface molecules affect both cytolytic activity and lymphocyte growth and activation. Monoclonal antibodies (mAbs) with specificity for HLA class I and class II molecules were generated which affect the lytic activity of a cloned line of human NK cells (NK 3.3). The HLA class I- specific mAb that augments lysis (mAb 131) has been characterized as a unique anti-HLA-A locus-specific mAb. In contrast, an anti-HLA-B locus-specific mAb (4E) inhibits killing, suggesting HLA class I-locus-specific effects on NK function. Similarly, the anti-HLA-A and anti-HLA-B locus-specific mAbs have differential effects on the activation of T and B lymphocytes by a variety of mitogens. Such functional differences in HLA-A and B locus-encoded gene products have not been previously described. These mAbs are thus valuable tools for understanding the role of MHC molecules in lymphocyte functions. The working hypothesis is: 1) MHC molecules associate with functionally important receptors in the membranes of NK cells, T cells and B cells, and 2) HLA-A locus and B locus gene products form different associations resulting in different functional effects of the antibodies directed against them. We will test this hypothesis by: 1) examining potential physical associations of MHC class I A and B locus-encoded molecules with other functionally important molecules on NK, T and B cells, 2) studying differential recycling and phosphorylation of MHC molecules in these cells, and 3) studying changes in early metabolic events and gene expression associated with activation or lytic activity in NK, T and B cells in the absence and presence of the anti-HLA and B locus-specific mAbs. These studies will provide further information on the role of the MHC in cellular functions, including growth, and provide greater insight into the mechanisms and regulation of lytic function and cellular proliferation.