In order to understand how the mammalian immune system provides protection against pathogens, it is important to understand the molecular basis of immune system function. CD244 is one of the receptors related to CD150 (SLAM) with the potential to bind the adaptors, SAP and EAT-2. It has recently been shown by the host laboratory that the outcome of engagement of these receptors depends on the context of the interactions, such as which other receptors are engaged, the level of activation, and between which cells. The overall goal of this project will be to establish a paradigm for the function of the family of CD150-related receptors. With an initial analysis of CD2 and CD244, and later inclusion of additional family members, a thorough understanding of how this family of receptors modulates leukocyte function will be developed. Our specific aims are as follows. First, we plan to explore the parameters which determine the overall effect of CD244 and CD2 engagement during an immune response. Using a human NK cell line expressing CD2 and CD244, and a mouse T-cell hybridoma, we will examine the effects of the engagement of these receptors and recruitment of SAP and EAT-2 on cytotoxicity and IFN-gamma production. Second we will perform in vivo experiments relating human data on CD244 function to a mouse tumour model, in which the in vivo activity of a CD244 blocking antibody will be used to analyze the effect of CD244 blockade in resistance to tumour growth. Finally, using surface plasmon resonance and recombinant proteins, we will establish a hierarchy of likely interactions of intracellular signalling molecules with additional members of the CD150 receptor family. Using the model system established in the first two aims, the predictions derived from the BIAcore experiments can be tested for functional accuracy, and a greater paradigm for the function of this receptor family can be established.
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