A Common Genetic Variation in Langerin (CD207) Compromises Cellular Uptake of Staphylococcus aureus

Langerhans cells are key sentinel cells of the skin and mucosal lining. They sense microorganisms through their repertoire of pattern-recognition receptors to mount and direct appropriate immune responses. We recently demonstrated that human Langerhans cells interact with the Gram-positive pathogen Staphylococcus aureus through the Langerhans cell-specific receptor langerin (CD207). It was previously hypothesized that two linked single nucleotide polymorphisms (SNPs; N288D and K313I) in the carbohydrate recognition domain of langerin would affect interaction with microorganisms. We show that recognition of S. aureus by recombinant langerin molecules is abrogated in the co-inheriting SNP variant, which is mainly explained by the N288D SNP and further enhanced by K313I. Moreover, introduction of SNP N288D in ectopically-expressed langerin affected cellular distribution of the receptor such that langerin displayed enhanced plasma membraneexpression. Despite this increased binding of S. aureus by the langerin double SNP variant, uptake of bacteria by this langerin variant was compromised. Our findings indicate that in a proportion of the human population, the recognition and uptake of S. aureus by Langerhans cells may be affected, which could have important consequences for proper immune activation and S. aureus-associated disease.