title: The Syk-NFAT-IL-2 Pathway in Dendritic Cells Is Required for Optimal Sterile Immunity Elicited by Alum Adjuvants.
abstract: Despite a long history and extensive usage of insoluble aluminum salts (alum) as vaccine adjuvants, the molecular mechanisms underpinning Ag-specific immunity upon vaccination remain unclear. Dendritic cells (DCs) are crucial initiators of immune responses, but little is known about the molecular pathways used by DCs to sense alum and, in turn, activate T and B cells. In this article, we show that alum adjuvanticity requires IL-2 specifically released by DCs, even when T cell secretion of IL-2 is intact. We demonstrate that alum, as well as other sterile particulates, such as uric acid crystals, induces DCs to produce IL-2 following initiation of actin-mediated phagocytosis that leads to Src and Syk kinase activation, Ca2+mobilization, and calcineurin-dependent activation of NFAT, the master transcription factor regulating IL-2 expression. Using chimeric mice, we show that DC-derived IL-2 is required for maximal Ag-specific proliferation of CD4+T cells and optimal humoral responses following alum-adjuvanted immunization. These data identify DC-derived IL-2 as a key mediator of alum adjuvanticity in vivo and the Src-Syk pathway as a potential leverage point in the rational design of novel adjuvants.
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.
authors.forename: Hanif Javanmard
authors.identifier: 0000-0002-1737-0388
authors.initials: HJ
authors.lastname: Khameneh
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.
authors.forename: Adrian W S
authors.initials: AW
authors.lastname: Ho
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.
authors.forename: Roberto
authors.initials: R
authors.lastname: Spreafico
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.
authors.forename: Heidi
authors.identifier: 0000-0002-1156-4106
authors.initials: H
authors.lastname: Derks
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore.
authors.forename: Hazel Q Y
authors.identifier: 0000-0001-5597-5372
authors.initials: HQ
authors.lastname: Quek
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore alessandra_mortellaro@immunol.a-star.edu.sg.
authors.forename: Alessandra
authors.identifier: 0000-0003-1744-2430
authors.initials: A
authors.lastname: Mortellaro
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000534:Alum Compounds / Q000494:pharmacology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007376:Interleukin-2 / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D050778:NFATC Transcription Factors / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D000072377:Syk Kinase / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D007376:Interleukin-2; D050778:NFATC Transcription Factors; C041524:aluminum sulfate; D000072377:Syk Kinase