Peptidases released by necrotic cells  control CD8+ T cell cross-priming.
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.
Jaba
J
Gamrekelashvili
Tamar
T
Kapanadze
Miaojun
M
Han
Josef
J
Wissing
Chi
C
Ma
Lothar
L
Jaensch
Michael P
MP
Manns
Todd
T
Armstrong
Elizabeth
E
Jaffee
Ayla O
AO
White
Deborah E
DE
Citrin
Firouzeh
F
Korangy
Tim F
TF
Greten
D056704:Adaptive Immunity; D000818:Animals; D045744:Cell Line, Tumor; D045142:Cross-Priming; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D005260:Female; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D009336:Necrosis / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*
D034741:RNA, Small Interfering; D010047:Ovalbumin; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100152:dipeptidyl peptidase III; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase