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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Vesicular Transport / deficiency
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / physiology*
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Adoptive Transfer
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Amino Acid Sequence
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Amyloid beta-Peptides / administration & dosage
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Amyloid beta-Peptides / immunology*
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Animals
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Antigen Presentation
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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CD28 Antigens / deficiency
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CD28 Antigens / immunology
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CD40 Ligand / deficiency
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CD40 Ligand / immunology
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Germinal Center / immunology
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Histocompatibility Antigens Class II / immunology
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Humans
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Immunoglobulin Class Switching / immunology*
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Immunoglobulin G / biosynthesis
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Immunoglobulin M / biosynthesis
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Lipopolysaccharide Receptors / immunology
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Liposomes
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Nude
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Molecular Sequence Data
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Ovalbumin / administration & dosage
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Ovalbumin / immunology
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Peptide Fragments / administration & dosage
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Peptide Fragments / immunology*
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Receptors, Antigen, B-Cell / immunology
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T-Lymphocytes / immunology
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Toll-Like Receptor 4 / deficiency
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / physiology*
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Vaccination
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Vaccines, Subunit / administration & dosage
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Vaccines, Subunit / immunology*
Substances
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Adaptor Proteins, Vesicular Transport
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Amyloid beta-Peptides
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CD28 Antigens
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Histocompatibility Antigens Class II
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Immunoglobulin G
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Immunoglobulin M
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Lipopolysaccharide Receptors
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Liposomes
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Peptide Fragments
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Receptors, Antigen, B-Cell
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TICAM-1 protein, mouse
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Vaccines, Subunit
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amyloid beta-protein (1-15)
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CD40 Ligand
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Ovalbumin