title: Vaccine adjuvants aluminum and monophosphoryl lipid A provide distinct signals to generate protective cytotoxic memory CD8 T cells.
abstract: Vaccines can greatly reduce the spread of and deaths from many infectious diseases. However, many infections have no successful vaccines. Better understanding of the generation of protective CD8 memory T cells by vaccination is essential for the rational design of new vaccines that aim to prime cellular immune responses. Here we demonstrate that the combination of two adjuvants that are currently licensed for use in humans can be used to prime long-lived memory CD8 T cells that protect mice from viral challenge. The universally used adjuvant, aluminum salts, primed long-lived memory CD8 T cells; however, effective cytotoxic T-cell differentiation occurred only in the presence of an additional adjuvant, monophosphoryl lipid A (MPL). MPL-induced IL-6 was required for cytotoxic differentiation. The IL-6 acted by inducing granzyme B production and reducing expression of inhibitory molecule PD1 on the surface of the primed CD8 T cells. CD8 memory T cells generated by antigen delivered with both aluminum salts and MPL provided significant protection from influenza A challenge. These adjuvants could be used in human vaccines to prime protective memory CD8 T cells.
authors.affiliation: The Howard Hughes Medical Institute and Integrated Department of Immunology, National Jewish Health, Denver, CO 80206, USA. macleodm@njhealth.org
authors.forename: Megan K L
authors.initials: MK
authors.lastname: MacLeod
authors.forename: Amy S
authors.initials: AS
authors.lastname: McKee
authors.forename: Alexandria
authors.initials: A
authors.lastname: David
authors.forename: Jieru
authors.initials: J
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: Mason
authors.forename: John W
authors.initials: JW
authors.lastname: Kappler
authors.forename: Philippa
authors.initials: P
authors.lastname: Marrack
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000534:Alum Compounds / Q000008:administration & dosage*; D000818:Animals; D017951:Antigen Presentation; D000954:Antigens, Surface / Q000096:biosynthesis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D002417:Cattle; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D009980:Influenza A virus / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019590:Nucleocapsid Proteins; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor; D016601:RNA-Binding Proteins / Q000008:administration & dosage / Q000276:immunology; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D022223:Vaccines, Subunit / Q000008:administration & dosage*; D014758:Viral Core Proteins / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D015850:Interleukin-6; D008050:Lipid A; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D016601:RNA-Binding Proteins; D022223:Vaccines, Subunit; D014758:Viral Core Proteins; D012710:Serum Albumin, Bovine; C041524:aluminum sulfate; D010047:Ovalbumin; C048436:monophosphoryl lipid A