A polymorphism in a phosphotyrosine signalling motif of CD229 (Ly9, SLAMF3) alters SH2 domain binding and T‐cell activation

Signalling lymphocyte activation molecule (SLAM) family members regulate activation and inhibition in the innate and adaptive immune systems. Genome‐wide association studies identified their genetic locus (1q23) as highly polymorphic and associated with susceptibility to systemic lupus erythematosus (SLE). Here we show that the Val(602) variant of the non‐synonymous single nucleotide polymorphism (SNP) rs509749 in the SLAM family member CD229 (Ly9, SLAMF3) has a two‐fold lower affinity compared with the SLE‐associated Met(602) variant for the small adaptor protein SAP. Comparison of the two variants in T‐cell lines revealed the Val(602) variant to be significantly more highly expressed than CD229 Met(602). Activation was diminished in cells expressing CD229 Val(602) compared with CD229 Met(602) as measured by up‐regulation of CD69. There was no correlation between homozygosity at rs509749 and activation in peripheral blood mononuclear cells from healthy donors. These findings identify potential mechanisms by which a single SNP can perturb fine‐tuning in the immune system with significant functional consequences.