Characterization of murine CD244 haplotypes with divergent function

SLAM受体家族正在成为免疫反应微调和 促进淋巴细胞：淋巴细胞之间的相互作用。它们既能起抑制作用，也能起刺激作用。 受体依赖于它们与关键信号适配器的关联，这些信号适配器结合到基于酪氨酸的基序 它们的细胞质尾巴。SLAM家族受体CD244在所有NK细胞上都有表达，并能够 调节NK细胞介导的细胞毒作用和细胞因子的分泌。在人类中，它的刺激功能是 完全依赖于与适配器SAP的关联。SAP功能的丧失也是一个原因 致命性综合症，XLP。我们最近发现，在小鼠体内，两种主要的单倍型(b和z)的 SLAM家族基因簇存在，单倍型分化与狼疮小鼠模型有关。 我们已经在这些单倍型的背景下研究了CD244的功能，并发现在 CD244基因座导致CD244的功能分化，其中z单倍型表现为激活，b 单倍型抑制信号。定义这些多态如何导致不同的CD244功能和 对NK细胞生物学的影响以及天然免疫和获得性免疫之间的界面 回应是我们的长期目标。我们建议在以下具体目标中解决这一问题： 1.阐明CD244功能分化的分子机制。2.生成 仅在CD244等位基因表达上存在差异的转基因小鼠品系。3.检查影响 分化的CD244在NK细胞对肿瘤的反应中的作用。

The SLAM family of receptors is emerging as key players in the fine tuning of immune responses and facilitating lymphocyte:lymphocyte interactions. They are able to function as either inhibitory or stimulatory receptors depending upon their association with key signaling adaptors that bind to tyrosine based motifs in their cytoplasmic tails. The SLAM family receptor, CD244 is expressed on all NK cells and is able to regulate NK cell mediated cytotoxicity and cytokine secretion. In the human, its stimulatory function is completely dependent on the association with the adaptor, SAP. The loss of SAP function also contributes to the fatal syndrome, XLP. We have recently found that in the mouse, two major haplotypes (b and z) of the SLAM family gene cluster exist and haplotype divergence has been associated with a murine model of lupus. We have studied CD244 function in the context of these haplotypes and found that polymorphisms at the CD244 locus result in divergent function of CD244 with the z haplotype exhibiting activating and the b haplotype inhibitory signaling. Defining how these polymorphisms lead to divergent CD244 function and the consequence of that on NK cell biology and the interface between the innate and adaptive immune responses are our long-term goals. We propose to address this in the following specific aims: 1. To elucidate the molecular mechanisms responsible for divergent CD244 function. 2. To generate transgenic mouse strains which differ solely in their expression of CD244 alleles. 3. To examine the affect of divergent CD244 function on NK cell responses to tumors.