2.50
Hdl Handle:
http://hdl.handle.net/10033/306696
Title:
Peptidases released by necrotic cells control CD8+ T cell cross-priming.
Authors:
Gamrekelashvili, Jaba; Kapanadze, Tamar; Han, Miaojun; Wissing, Josef; Ma, Chi; Jaensch, Lothar; Manns, Michael P; Armstrong, Todd; Jaffee, Elizabeth; White, Ayla O; Citrin, Deborah E; Korangy, Firouzeh; Greten, Tim F
Abstract:
Cross-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.
Citation:
Peptidases released by necrotic cells control CD8+ T cell cross-priming. 2013: J. Clin. Invest.
Journal:
The Journal of clinical investigation
Issue Date:
8-Oct-2013
URI:
http://hdl.handle.net/10033/306696
DOI:
10.1172/JCI65698
PubMed ID:
24216478
Type:
Article
ISSN:
1558-8238
Appears in Collections:
publications of the research group cellular proteom research (CPRO)

Full metadata record

DC FieldValue Language
dc.contributor.authorGamrekelashvili, Jabaen
dc.contributor.authorKapanadze, Tamaren
dc.contributor.authorHan, Miaojunen
dc.contributor.authorWissing, Josefen
dc.contributor.authorMa, Chien
dc.contributor.authorJaensch, Lotharen
dc.contributor.authorManns, Michael Pen
dc.contributor.authorArmstrong, Todden
dc.contributor.authorJaffee, Elizabethen
dc.contributor.authorWhite, Ayla Oen
dc.contributor.authorCitrin, Deborah Een
dc.contributor.authorKorangy, Firouzehen
dc.contributor.authorGreten, Tim Fen
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.en
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

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