Defining How Polymorphisms at the Slam Family Locus Affect NK and T Cell Function
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Sequence analysis of the SLAM family of receptors identified two stable haplotypes found in common laboratory strains of mice. The b haplotype is found in all C57-derived mouse strains, and the z haplotype is found in all non-C57 derived mouse strains, including many autoimmune mouse strains. The SLAM family of receptors, which includes CD244, Ly108, CD84, CD48, CD229, and Cs1, are involved in regulating several immune functions such as cellular activation, cytokine secretion, cytotoxicity, and apoptosis. Thus, it is not surprising that dysregulation of this family of receptors is associated with disease states such as systemic lupus erythematosus (SLE) and X-linked lymphoproliferative disease (XLP). The antinuclear autoantibody (ANA) causative locus, Sle1b, in the NZM2410 mouse model of lupus has been shown to contain the entire SLAM family (SF) locus. Whereas, XLP is caused by mutations in a critical adaptor protein, SAP, leading to defective SF signaling. This dissertation is based on the premise that polymorphisms at the SF locus alter SF function in lymphocytes. To address this, we compared lymphocyte function in B6 mice, which contain the b haplotype of the SF, and B6.Sle1b mice that are congenic for the 900 kb interval surrounding the z haplotype of the SF. Thus, differences in lymphocyte function can be directly attributed to polymorphism at the SF locus. These congenic mouse strains were used in two studies: 1) to characterize the function of CD244 in NK cells, and 2) to characterize CD4+ T cell function. We show that polymorphisms in CD244 alter receptor function, where engagement of the z allele of CD244 results in increased cytotoxicity dependent on SAP expression. In contrast, engagement of the b allele of CD244 predominately results in inhibition of cytotoxicity, independent of SAP expression. These studies may explain previously conflicting data describing CD244 function. Our studies characterizing CD4+ T cell function determined that polymorphisms at the SF locus result in altered SF expression, decreased IFN-gamma , IL-4, IL-5, IL-6, and IL-10 secretion, increased and prolonged CD40L expression, and altered SAP expression. In conclusion, we show that polymorphisms at the SF locus alter NK and T cell lymphocyte function.