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dc.contributor.authorGamrekelashvili, Jaba
dc.contributor.authorKapanadze, Tamar
dc.contributor.authorHan, Miaojun
dc.contributor.authorWissing, Josef
dc.contributor.authorMa, Chi
dc.contributor.authorJaensch, Lothar
dc.contributor.authorManns, Michael P
dc.contributor.authorArmstrong, Todd
dc.contributor.authorJaffee, Elizabeth
dc.contributor.authorWhite, Ayla O
dc.contributor.authorCitrin, Deborah E
dc.contributor.authorKorangy, Firouzeh
dc.contributor.authorGreten, Tim F
dc.date.accessioned2013-12-11T14:58:48Z
dc.date.available2013-12-11T14:58:48Z
dc.date.issued2013-10-08
dc.identifier.citationPeptidases released by necrotic cells control CD8+ T cell cross-priming. 2013: J. Clin. Invest.en
dc.identifier.issn1558-8238
dc.identifier.pmid24216478
dc.identifier.doi10.1172/JCI65698
dc.identifier.urihttp://hdl.handle.net/10033/306696
dc.description.abstractCross-priming of CD8+ T cells and generation of effector immune responses is pivotal for tumor immunity as well as for successful anticancer vaccination and therapy. Dead and dying cells produce signals that can influence Ag processing and presentation; however, there is conflicting evidence regarding the immunogenicity of necrotic cell death. We used a mouse model of sterile necrosis, in which mice were injected with sterile primary necrotic cells, to investigate a role of these cells in priming of CD8+ T cells. We discovered a molecular mechanism operating in Ag donor cells that regulates cross-priming of CD8+ T cells during primary sterile necrosis and thereby controls adaptive immune responses. We found that the cellular peptidases dipeptidyl peptidase 3 (DPP-3) and thimet oligopeptidase 1 (TOP-1), both of which are present in nonimmunogenic necrotic cells, eliminated proteasomal degradation products and blocked Ag cross-presentation. While sterile necrotic tumor cells failed to induce CD8+ T cell responses, their nonimmunogenicity could be reversed in vitro and in vivo by inactivation of DPP-3 and TOP-1. These results indicate that control of cross-priming and thereby immunogenicity of primary sterile necrosis relies on proteasome-dependent oligopeptide generation and functional status of peptidases in Ag donor cells.
dc.languageENG
dc.rightsArchived with thanks to The Journal of clinical investigationen
dc.titlePeptidases released by necrotic cells control CD8+ T cell cross-priming.
dc.typeArticleen
dc.identifier.journalThe Journal of clinical investigationen
refterms.dateFOA2018-06-13T07:23:11Z
html.description.abstractCross-priming of CD8+ T cells and generation of effector immune responses is pivotal for tumor immunity as well as for successful anticancer vaccination and therapy. Dead and dying cells produce signals that can influence Ag processing and presentation; however, there is conflicting evidence regarding the immunogenicity of necrotic cell death. We used a mouse model of sterile necrosis, in which mice were injected with sterile primary necrotic cells, to investigate a role of these cells in priming of CD8+ T cells. We discovered a molecular mechanism operating in Ag donor cells that regulates cross-priming of CD8+ T cells during primary sterile necrosis and thereby controls adaptive immune responses. We found that the cellular peptidases dipeptidyl peptidase 3 (DPP-3) and thimet oligopeptidase 1 (TOP-1), both of which are present in nonimmunogenic necrotic cells, eliminated proteasomal degradation products and blocked Ag cross-presentation. While sterile necrotic tumor cells failed to induce CD8+ T cell responses, their nonimmunogenicity could be reversed in vitro and in vivo by inactivation of DPP-3 and TOP-1. These results indicate that control of cross-priming and thereby immunogenicity of primary sterile necrosis relies on proteasome-dependent oligopeptide generation and functional status of peptidases in Ag donor cells.


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