title: Human CD1a deficiency is common and genetically regulated.
abstract: CD1 proteins evolved to present diverse lipid Ags to T cells. In comparison with MHC proteins, CD1 proteins exhibit minimal allelic diversity as a result of nonsynonymous single nucleotide polymorphisms (SNPs). However, it is unknown if common SNPs in gene regulatory regions affect CD1 expression and function. We report surprising diversity in patterns of inducible CD1a expression on human dendritic cells (DCs), spanning the full range from undetectable to high density, a finding not seen with other CD1 isoforms. CD1a-deficient DCs failed to present mycobacterial lipopeptide to T cells but had no defects in endocytosis, cytokine secretion, or expression of costimulatory molecules after LPS treatment. We identified an SNP in the 5' untranslated region (rs366316) that was common and strongly associated with low CD1a surface expression and mRNA levels (p = 0.03 and p = 0.001, respectively). Using a CD1a promoter-luciferase system in combination with mutagenesis studies, we found that the polymorphic allele reduced luciferase expression by 44% compared with the wild-type variant (p < 0.001). Genetic regulation of lipid Ag presentation by varying expression on human DCs provides a mechanism for achieving population level differences in immune responses despite limited structural variation in CD1a proteins.
authors.affiliation: Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98195, USA. seshadri@u.washington.edu
authors.forename: Chetan
authors.initials: C
authors.lastname: Seshadri
authors.forename: Meera
authors.initials: M
authors.lastname: Shenoy
authors.forename: Richard D
authors.initials: RD
authors.lastname: Wells
authors.forename: Tiffany
authors.initials: T
authors.lastname: Hensley-McBain
authors.forename: Erica
authors.initials: E
authors.lastname: Andersen-Nissen
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.forename: Tan-Yun
authors.initials: TY
authors.lastname: Cheng
authors.forename: D Branch
authors.initials: DB
authors.lastname: Moody
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hawn
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D018949:Antigens, CD1 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D004705:Endocytosis; D004926:Escherichia coli / Q000276:immunology; D005260:Female; D017930:Genes, Reporter; D014644:Genetic Variation; D006801:Humans; D055666:Lipopeptides / Q000276:immunology*; D008070:Lipopolysaccharides / Q000627:therapeutic use; D008297:Male; D016297:Mutagenesis, Site-Directed; D009169:Mycobacterium tuberculosis / Q000276:immunology; D010080:Oxazoles / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D020121:5' Untranslated Regions; D018949:Antigens, CD1; C419393:CD1a antigen; D016207:Cytokines; D055666:Lipopeptides; D008070:Lipopolysaccharides; D010080:Oxazoles; D012333:RNA, Messenger; C585579:dideoxymycobactin