title: Cathepsin-mediated necrosis controls the adaptive immune response by Th2 (T helper type 2)-associated adjuvants.
abstract: Immunologic adjuvants are critical components of vaccines, but it remains unclear how prototypical adjuvants enhance the adaptive immune response. Recent studies have shown that 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. We demonstrated that direct lysosome-permeabilization with a soluble peptide, Leu-Leu-OMe, mimics the alum-like 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-like immune response 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.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Jacobson
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Heriberto
authors.initials: H
authors.lastname: Lima
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Goldberg
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering, New York, New York 10065.
authors.forename: Vasilena
authors.initials: V
authors.lastname: Gocheva
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Tsiperson
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52241.
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering, New York, New York 10065.
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Joyce
authors.affiliation: Department of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Bianca V
authors.initials: BV
authors.lastname: Gapp
authors.affiliation: Department of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Blomen
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Kartik
authors.initials: K
authors.lastname: Chandran
authors.affiliation: Department of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Thijn R
authors.initials: TR
authors.lastname: Brummelkamp
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Felipe
authors.initials: F
authors.lastname: Diaz-Griffero
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461. Electronic address: jurgen.brojatsch@einstein.yu.edu.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brojatsch
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism*; D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D020789:Cathepsin C / Q000494:pharmacology; D002403:Cathepsins / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D005260:Female; D006098:Granulocytes / Q000166:cytology; D007107:Immune System; D007113:Immunity, Innate; D007249:Inflammation; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009336:Necrosis; D010455:Peptides / Q000737:chemistry; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D018418:Th2 Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D010455:Peptides; D002403:Cathepsins; D020789:Cathepsin C; D020170:Caspase 1