Origination of New Immunological Functions in the Costimulatory Molecule B7-H3 The Role of Exon Duplication in Evolution of the Immune System 英文参考文献.docVIP

OriginationofNewImmunologicalFunctionsinthe CostimulatoryMoleculeB7-H3:TheRoleofExon DuplicationinEvolutionoftheImmuneSystem JingSun2.,FengqingFu1,4.,WenchaoGu1,3,RuhongYan1,4,GuangboZhang3,4,ZhiyongShen1 ,Yinghui Zhou1,HanWang5,BairongShen6*,XueguangZhang1,3,4* 1InstituteofMedicalBiotechnology,SoochowUniversity,Suzhou,China,2SuzhouHealthTechnologyCollege,Suzhou,China,3StemCellResearchLaboratoryofJiangsu Province, Suzhou, China, 4Clinical Immunology Laboratory, First Affiliated Hospital, Suzhou, China, 5Laboratory of Developmental Genetics and Genomics Medical College,SoochowUniversity,Suzhou,China,6CenterforSystemsBiology,SoochowUniversity,Suzhou,China Abstract B7-H3,arecentlyidentifiedB7familymember,hasdifferentisoformsinhumanandmouse.MouseB7-H3genehasonlyone isoform(2IgB7-H3)withtwoIg-likedomains,whereashumanB7-H3hastwoisoforms(2IgB7-H3and4IgB7-H3).Inthisstudy asystematicgenomic survey across various species from teleost fishes tomammals revealedthat4IgB7-H3 isoformalso appearedinpigs,guineapigs,cows,dogs,Africanelephants,pandas,megabatsandhigherprimateanimals,whichresulted fromtandemexonduplication.Furthersequenceanalysisindicatedthatthisduplicationgeneratedanewconservedregion in the first IgC domain, which might disable 4IgB7-H3 from releasing soluble form, while 2IgB7-H3 presented both membraneandsolubleforms.Throughthree-dimensional(3D)structuremodelingandfusion-proteinbindingassays,we discoveredthattheduplicatedisoformhadadifferentstructureandmightbindtoanotherpotentialreceptoronactivated T cells. In T cell proliferation assay, human 2IgB7-H3 (h2IgB7-H3) and mouse B7-H3 (mB7-H3) both increased T cell proliferation and IL-2, IFN-c production, whereas human 4IgB7-H3 (h4IgB7-H3) reduced cytokine production and T cell proliferationcomparedtocontrol.Furthermore,bothh2IgB7-H3andmB7-H3upregulatedthefunctionoflipopolysacharide (LPS)-activatedmonocyteinvitro.Takentogether,ourdataimpliedthatduringtheevolutionofvertebrates,B7-H3exon duplicationcontributedtothegenera