Abstract
Epidemiological studies have suggested that the recent increase in the incidence and severity of immunoglobulin (Ig)E-mediated allergic disorders is inversely correlated with Mycobacterium bovis bacillus Calmette Guerin (BCG) vaccination; however, the underlying mechanisms remain uncertain. Here, we demonstrate that natural killer T (NKT) cells in mice and humans play a crucial role in the BCG-induced suppression of IgE responses. BCG-activated murine Valpha14 NKT cells, but not conventional CD4 T cells, selectively express high levels of interleukin (IL)-21, which preferentially induces apoptosis in Bepsilon cells. Signaling from the IL-21 receptor increases the formation of a complex between Bcl-2 and the proapoptotic molecule Bcl-2-modifying factor, resulting in Bepsilon cell apoptosis. Similarly, BCG vaccination induces IL-21 expression by human peripheral blood mononuclear cells (PBMCs) in a partially NKT cell-dependent fashion. BCG-activated PBMCs significantly reduce IgE production by human B cells. These findings provide new insight into the therapeutic effect of BCG in allergic diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antibodies, Monoclonal / pharmacology
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Antibody Formation / immunology
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Antigens, CD1 / immunology
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Antigens, CD1d
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Apoptosis / immunology*
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Female
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Gene Expression
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Humans
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Immunoglobulin E / blood
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Immunoglobulin E / immunology*
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Interleukin-12 / genetics
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Interleukin-12 / metabolism
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Interleukin-12 / pharmacology
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Interleukin-21
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Interleukins / physiology*
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Liver / immunology
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Liver / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Monocytes, Activated Killer / immunology
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Mycobacterium bovis / immunology
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Ovalbumin / immunology
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies, Monoclonal
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Antigens, CD1
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Antigens, CD1d
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Bmf protein, mouse
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CD1D protein, human
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Interleukins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Antigen, T-Cell, alpha-beta
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Interleukin-12
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Immunoglobulin E
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Ovalbumin
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Interleukin-21