Cathepsin-mediated necrosis controls the adaptive immune response by Th2 (T helper type 2)-associated adjuvants

Lee S. Jacobson, Heriberto Lima, Michael F. Goldberg, Vasilena Gocheva, Vladislav Tsiperson, Fayyaz S. Sutterwala, Johanna A. Joyce, Bianca V. Gapp, Vincent A. Blomen, Kartik Chandran, Thijn R. Brummelkamp, Felipe Diaz-Griffero, Jürgen Brojatsch

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Abstract

Immunologic adjuvants are critical components of vaccines, but it remains unclear how prototypical adjuvants enhance the adaptiveimmuneresponse. Recentstudieshaveshownthat necrotic cells could trigger an immune response. Although most adjuvants have been shown to be cytotoxic, this activity has traditionally been considered a side effect. We set out to test the role of adjuvant-mediated cell death in immunity and found that alum, the most commonly used adjuvant worldwide, triggers a novel form of cell death in myeloid leukocytes characterized by cathepsin-dependent lysosome-disruption. Wedemonstrated that direct lysosome-permeabilization with a soluble peptide, Leu-Leu-OMe, mimics the alumlike form of necrotic cell death in terms of cathepsin dependence and cell-type specificity. Using a combination of a haploid genetic screen and cathepsin-deficient cells, we identified specific cathepsins that control lysosome-mediated necrosis. We identified cathepsin C as critical for Leu-Leu-OMe-induced cell death, whereas cathepsins B and S were required for alum-mediated necrosis. Consistent with a role of necrotic cell death in adjuvant effects, Leu-Leu-OMe replicated an alum-likeimmuneresponse in vivo, characterized by dendritic cell activation, granulocyte recruitment, and production of Th2-associated antibodies. Strikingly, cathepsin C deficiency not only blocked Leu-Leu-OMe-mediated necrosis but also impaired Leu-Leu-OMe-enhanced immunity. Together our findings suggest that necrotic cell death is a powerful mediator of a Th2-associated immune response.

Original languageEnglish (US)
Pages (from-to)7481-7491
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number11
DOIs
StatePublished - Mar 15 2013

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Cathepsins
Adaptive Immunity
Cell death
Cell Death
Necrosis
Cathepsin C
Lysosomes
cathepsin S
Immunity
Immunologic Adjuvants
Cathepsin B
Haploidy
Granulocytes
Dendritic Cells
Leukocytes
Vaccines
Chemical activation
leucyl-leucine-methyl ester
Peptides
Antibodies

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Jacobson, L. S., Lima, H., Goldberg, M. F., Gocheva, V., Tsiperson, V., Sutterwala, F. S., ... Brojatsch, J. (2013). Cathepsin-mediated necrosis controls the adaptive immune response by Th2 (T helper type 2)-associated adjuvants. Journal of Biological Chemistry, 288(11), 7481-7491. https://doi.org/10.1074/jbc.M112.400655

Cathepsin-mediated necrosis controls the adaptive immune response by Th2 (T helper type 2)-associated adjuvants. / Jacobson, Lee S.; Lima, Heriberto; Goldberg, Michael F.; Gocheva, Vasilena; Tsiperson, Vladislav; Sutterwala, Fayyaz S.; Joyce, Johanna A.; Gapp, Bianca V.; Blomen, Vincent A.; Chandran, Kartik; Brummelkamp, Thijn R.; Diaz-Griffero, Felipe; Brojatsch, Jürgen.

In: Journal of Biological Chemistry, Vol. 288, No. 11, 15.03.2013, p. 7481-7491.

Research output: Contribution to journalArticle

Jacobson, LS, Lima, H, Goldberg, MF, Gocheva, V, Tsiperson, V, Sutterwala, FS, Joyce, JA, Gapp, BV, Blomen, VA, Chandran, K, Brummelkamp, TR, Diaz-Griffero, F & Brojatsch, J 2013, 'Cathepsin-mediated necrosis controls the adaptive immune response by Th2 (T helper type 2)-associated adjuvants', Journal of Biological Chemistry, vol. 288, no. 11, pp. 7481-7491. https://doi.org/10.1074/jbc.M112.400655
Jacobson, Lee S. ; Lima, Heriberto ; Goldberg, Michael F. ; Gocheva, Vasilena ; Tsiperson, Vladislav ; Sutterwala, Fayyaz S. ; Joyce, Johanna A. ; Gapp, Bianca V. ; Blomen, Vincent A. ; Chandran, Kartik ; Brummelkamp, Thijn R. ; Diaz-Griffero, Felipe ; Brojatsch, Jürgen. / Cathepsin-mediated necrosis controls the adaptive immune response by Th2 (T helper type 2)-associated adjuvants. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 11. pp. 7481-7491.
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AU - Gapp, Bianca V.

AU - Blomen, Vincent A.

AU - Chandran, Kartik

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