Peptidases released by necrotic cells control CD8+ T cell cross-priming
Jaba Gamrekelashvili, … , Firouzeh Korangy, Tim F. Greten
Jaba Gamrekelashvili, … , Firouzeh Korangy, Tim F. Greten
Published October 8, 2013
Citation Information: J Clin Invest. 2013;123(11):4755-4768. https://doi.org/10.1172/JCI65698.
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Research Article Immunology

Peptidases released by necrotic cells control CD8+ T cell cross-priming

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.

Authors

Jaba Gamrekelashvili, Tamar Kapanadze, Miaojun Han, Josef Wissing, Chi Ma, Lothar Jaensch, Michael P. Manns, Todd Armstrong, Elizabeth Jaffee, Ayla O. White, Deborah E. Citrin, Firouzeh Korangy, Tim F. Greten

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Figure 1

Primary FT necrotic cells do not induce CD8+ T cell activation.

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Primary FT necrotic cells do not induce CD8+ T cell activation. (A) On...
(A) On days 0 and 2, splenic CD11c+ DCs were pulsed with SF of B78OVA-FT or B78OVA-FTheat cells. DCs were washed and injected into mice. On day 7, recipients were challenged with live B16OVA, and tumor growth was monitored. Data are from 2 independent experiments (n = 8–10 per group). P < 0.0001, log-rank (Mantel-Cox) test. (B and C) Mice were vaccinated as in A, and OVA-specific lysis (B) and percent OVA-specific CD8+ T cells (C) in draining LNs (DLN) and spleens (SPL) were determined on day 7. Data are from 1 representative of 2 experiments (n = 3 per group). (D and E) Mice were vaccinated with 5 × 106 B78OVA-FT or B78OVA-FTheat cells on days 0 and 2. On day 7, OVA-specific lysis (D) and percent tetramer-positive cells (E) was determined. Data are representative of 3 experiments (n = 3 per group). (F–H) SF from B78OVA-FT was incubated at 70°C (FTheat) and cultured in vitro with OT-I splenocytes. Proliferation and IFN-γ expression of CD8+ T cells was analyzed after 48 hours. (F) IFN-γ release by proliferating CD8+ OT-I cells. (G and H) Corresponding cumulative results. Data are representative of 3 independent experiments. (I) S8L or B78OVA-FTheat cells (2.5 × 105) were cultured with OVA-specific CFSE-labeled CD8+ T cells with or without CD11c+ DCs, and T cell proliferation was analyzed. Results are representative of 3 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, Student’s t test.