title: TLR4- and TRIF-dependent stimulation of B lymphocytes by peptide liposomes enables T cell-independent isotype switch in mice.
abstract: Immunoglobulin class switching from IgM to IgG in response to peptides is generally T cell-dependent and vaccination in T cell-deficient individuals is inefficient. We show that a vaccine consisting of a dense array of peptides on liposomes induced peptide-specific IgG responses totally independent of T-cell help. Independency was confirmed in mice lacking T cells and in mice deficient for MHC class II, CD40L, and CD28. The IgG titers were high, long-lived, and comparable with titers obtained in wild-type animals, and the antibody response was associated with germinal center formation, expression of activation-induced cytidine deaminase, and affinity maturation. The T cell-independent (TI) IgG response was strictly dependent on ligation of TLR4 receptors on B cells, and concomitant TLR4 and cognate B-cell receptor stimulation was required on a single-cell level. Surprisingly, the IgG class switch was mediated by TIR-domain-containing adapter inducing interferon-β (TRIF), but not by MyD88. This study demonstrates that peptides can induce TI isotype switching when antigen and TLR ligand are assembled and appropriately presented directly to B lymphocytes. A TI vaccine could enable efficient prophylactic and therapeutic vaccination of patients with T-cell deficiencies and find application in diseases where induction of T-cell responses contraindicates vaccination, for example, in Alzheimer disease.
authors.affiliation: AC Immune SA, Parc Scientifique EPFL B, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Pihlgren
authors.forename: Alberto B
authors.initials: AB
authors.lastname: Silva
authors.forename: Rime
authors.initials: R
authors.lastname: Madani
authors.forename: Valérie
authors.initials: V
authors.lastname: Giriens
authors.forename: Ying
authors.initials: Y
authors.lastname: Waeckerle-Men
authors.forename: Antonia
authors.initials: A
authors.lastname: Fettelschoss
authors.forename: David T
authors.initials: DT
authors.lastname: Hickman
authors.forename: María Pilar
authors.initials: MP
authors.lastname: López-Deber
authors.forename: Dorin Mlaki
authors.initials: DM
authors.lastname: Ndao
authors.forename: Marija
authors.initials: M
authors.lastname: Vukicevic
authors.forename: Anna Lucia
authors.initials: AL
authors.lastname: Buccarello
authors.forename: Valérie
authors.initials: V
authors.lastname: Gafner
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chuard
authors.forename: Pedro
authors.initials: P
authors.lastname: Reis
authors.forename: Kasia
authors.initials: K
authors.lastname: Piorkowska
authors.forename: Andrea
authors.initials: A
authors.lastname: Pfeifer
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kündig
authors.forename: Andreas
authors.initials: A
authors.lastname: Muhs
authors.forename: Pål
authors.initials: P
authors.lastname: Johansen
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018106:CD28 Antigens / Q000172:deficiency / Q000276:immunology; D023201:CD40 Ligand / Q000172:deficiency / Q000276:immunology; D018858:Germinal Center / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008081:Liposomes; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014611:Vaccination; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D018106:CD28 Antigens; D023201:CD40 Ligand; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D018950:Lipopolysaccharide Receptors; D008081:Liposomes; D010047:Ovalbumin; D010446:Peptide Fragments; D011947:Receptors, Antigen, B-Cell; D051197:Toll-Like Receptor 4; D022223:Vaccines, Subunit; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C480626:amyloid beta-protein (1-15)