A Novel Mechanism of Soluble HLA-G Mediated Immune Modulation Downregulation of T Cell Chemokine Receptor Expression and Impairment of Chemotaxis 英文参考文献.docVIP

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A Novel Mechanism of Soluble HLA-G Mediated Immune Modulation Downregulation of T Cell Chemokine Receptor Expression and Impairment of Chemotaxis 英文参考文献.doc

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A Novel Mechanism of Soluble HLA-G Mediated Immune Modulation Downregulation of T Cell Chemokine Receptor Expression and Impairment of Chemotaxis 英文参考文献

ANovelMechanismofSolubleHLA-GMediatedImmune Modulation:DownregulationofTCellChemokine ReceptorExpressionandImpairmentofChemotaxis FabioMorandi*,ElisaFerretti,PaolaBocca,IgnaziaPrigione,LizziaRaffaghello,VitoPistoia LaboratoryofOncology,G.GasliniChildren’sHospital,Genoa,Italy Abstract Background: In recent years, many immunoregulatory functions have been ascribed to soluble HLA-G (sHLA-G). Since chemotaxis is crucial for an efficient immune response, we have investigated for the first time the effects of sHLA-G on chemokinereceptorexpressionandfunctionindifferenthumanTcellpopulations. Methodology/Principal Findings: T cell populations isolated from peripheral blood were stimulated in the presence or absenceofsHLA-G.Chemokinereceptorsexpressionwasevaluatedbyflowcytometry.sHLA-Gdownregulatedexpression + + ofi)CCR2,CXCR3andCXCR5inCD4 Tcells,ii)CXCR3inCD8 Tcells,iii)CXCR3inTh1clonesiv)CXCR3inTCRVd2c9Tcells, andupregulated CXCR4 expressioninTCRVd2c9 Tcells. sHLA-G inhibitedin vitrochemotaxis of i) CD4 Tcells towards + + CCL2,CCL8,CXCL10andCXCL11,ii)CD8 TcellstowardsCXCL10andCXCL11,iii)Th1clonestowardsCXCL10,andiv)TCR Vd2c9TcellstowardsCXCL10andCXCL11.DownregulationofCXCR3expressiononCD4+TcellsbysHLA-Gwaspartially revertedbyaddingablockingantibodyagainstILT2/CD85j,areceptorforsHLA-G,suggestingthatsHLA-Gdownregulated chemokinereceptorexpressionmainlythroughtheinteractionwithILT2/CD85j.FollicularhelperTcells(TFH)wereisolated fromhumantonsilsandstimulatedasdescribedabove.sHLA-GimpairedCXCR5expressioninTFHandchemotaxisofthe lattercellstowardsCXCL13.Moreover,sHLA-Gexpressionwasdetectedintonsilsbyimmunohistochemistry,suggestinga roleofsHLA-GinlocalcontrolofT cellchemotaxis.IntracellularpathwayswereinvestigatedbyWesternBlotanalysison FH total extracts from CD4+ T cells. Phosphorylation of Stat5, p70 s6k, b-arrestin and SHP2 was modulated by sHLA-G treatment. Conclusions/Significance:OurdatademonstratedthatsHLA-Gimpairsexpressionandfunctionalityofdifferentchemokine