Annexin A1 on the Surface of Early Apoptotic Cells Suppresses CD8+ T Cell Immunity.docVIP

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Annexin A1 on the Surface of Early Apoptotic Cells Suppresses CD8+ T Cell Immunity.doc

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AnnexinA1ontheSurfaceofEarlyApoptoticCellsSuppressesCD8TCellImmunity

AnnexinA1ontheSurfaceofEarlyApoptoticCells SuppressesCD8 TCellImmunity + HeikoWeyd1,LucieAbeler-Do¨rner1.¤a,Bjo¨rnLinke1.,AndreaMahr1.¤b,VeronikaJahndel1, SandraPfrang1,MartinaSchno¨lzer2,ChristineS.Falk3,PeterH.Krammer1* 1Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany, 2Functional Proteome Analysis, German Cancer Research Center, Heidelberg, Germany,3InstituteforTransplantImmunology,HannoverMedicalSchool,Hanover,Germany Abstract Preventionofanimmuneresponseagainstself-antigensderivedfromapoptoticcellsisessentialtoprecludeautoimmune andchronicinflammatorydiseases.Here,wedescribeapoptosisinducedexternalizationofendogenouscytosolicannexin1 initiating an anti-inflammatory effector mechanism that suppresses the immune response against antigens of apoptotic cells. Cytosolic annexin 1 rapidly translocated to the apoptotic cell surface and inhibited dendritic cell (DC) activation induced by Toll like receptors (TLR). Annexin 1-inhibited DC showed strongly reduced secretion of pro-inflammatory cytokines(e.g.TNFandIL-12)andcostimulatorysurfacemolecules(e.g.CD40andCD86),whileanti-inflammatorymediators likePD-L1remainedunchanged.TcellsstimulatedbysuchDClackedsecretionofinterferon-c(IFN-c)andTNFbutretained IL-10secretion.Inmice,annexin1preventedthedevelopmentofinflammatoryDCandsuppressedthecellularimmune responseagainstthemodelantigenovalbumin(OVA)expressedinapoptoticcells.Furthermore,annexin1onapoptotic cellscompromisedOVA-specifictumorvaccinationandimpairedrejectionofanOVA-expressingtumor.Thus,ourresults provideamolecularmechanismforthesuppressiveactivityofapoptoticcellsontheimmuneresponsetowardsapoptotic cell-derived self-antigens. This process may play an important role in prevention of autoimmune diseases and of the immuneresponseagainstcancer. Citation: Weyd H, Abeler-Do¨rner L, Linke B, Mahr A, Jahndel V, et al. (2013) Annexin A1 on the Surface of Early Apoptotic Cells Suppresses CD8+ T Cell Immunity.PLoSONE8(4):e62449.doi:10.1371/journal