Delineating the Role of CD244 in NK Cell Cytotoxicity and the Contribution of Ly108 to Thymocyte Development

Genetic analysis of the a murine model of lupus has implicated polymorphisms in the SLAM family of receptors (CD244 (2B4), CD229 (Ly9), CS-1 (CRACC), CD48 CD150 (SLAM), CD84, and Ly108 (NTB-A)) as causative for a breach in tolerance of both T and B cells leading to the production of self reactive antibodies. Analysis of common strains of laboratory mice revealed the existence of two stable haplotypes (b and z) of the SLAM family gene cluster. Given recent studies identifying polymorphisms in the SLAM family in humans, we have determined how polymorphisms in the SLAM family can affect lymphocyte function in mice to model how similar mechanisms may be involved in human pathologies. For these studies, we used mice congenic at the SLAM family locus (B6 –b haplotype and B6.Sle1b–z haplotype) to study two major questions: 1.) how do polymorphisms in CD244 affect NK function? And 2.) how do polymorphisms in Ly108 affect T cell tolerance? In the studies presented herein we demonstrate that CD244 functions largely as an inhibitory receptor in NK cells from B6 mice and as an activating receptor in B6.Sle1b mice. We demonstrate that allelic polymorphisms contribute to this differential function by altering receptor isoform usage, cell surface densities, baseline phosphorylation levels and subsequent adaptor association and receptor downmodulation.

We also demonstrate that differential isoform usage of the receptor, Ly108 in B6 and B6.Sle1b mice alters thymocyte differentiation and negative selection events leading to a break in tolerance of T cells in B6.Sle1b mice. This is due to differential affects of the isoforms of Ly108 on thymocyte cell cycle progression and sensitivity to apoptosis. These studies highlight how naturally occurring polymorphisms in SLAM family genes can profoundly affect receptor function and potentially result in pathologic outcomes in certain genetic contexts.