TY - JOUR
T1 - Cathepsin-mediated necrosis controls the adaptive immune response by Th2 (T helper type 2)-associated adjuvants
AU - Jacobson, Lee S.
AU - Lima, Heriberto
AU - Goldberg, Michael F.
AU - Gocheva, Vasilena
AU - Tsiperson, Vladislav
AU - Sutterwala, Fayyaz S.
AU - Joyce, Johanna A.
AU - Gapp, Bianca V.
AU - Blomen, Vincent A.
AU - Chandran, Kartik
AU - Brummelkamp, Thijn R.
AU - Diaz-Griffero, Felipe
AU - Brojatsch, Jürgen
PY - 2013/3/15
Y1 - 2013/3/15
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M112.400655
DO - 10.1074/jbc.M112.400655
M3 - Article
C2 - 23297415
AN - SCOPUS:84875145230
SN - 0021-9258
VL - 288
SP - 7481
EP - 7491
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 11
ER -