IL-21-induced Bepsilon cell apoptosis mediated by natural killer T cells suppresses IgE responses.
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.
Harada
Michishige
M
Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
Magara-Koyanagi
Kumiko
K
Watarai
Hiroshi
H
Nagata
Yuko
Y
Ishii
Yasuyuki
Y
Kojo
Satoshi
S
Horiguchi
Shigetoshi
S
Okamoto
Yoshitaka
Y
Nakayama
Toshinori
T
Suzuki
Nobutaka
N
Yeh
Wen-Chen
WC
Akira
Shizuo
S
Kitamura
Hiroshi
H
Ohara
Osamu
O
Seino
Ken-ichiro
K
Taniguchi
Masaru
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000917:Antibody Formation / Q000276:immunology; D018949:Antigens, CD1 / Q000276:immunology; D055610:Antigens, CD1d; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007378:Interleukins / Q000502:physiology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016260:Monocytes, Activated Killer / Q000276:immunology; D009163:Mycobacterium bovis / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000098546:Interleukin-21
D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D018949:Antigens, CD1; D055610:Antigens, CD1d; C435486:Bmf protein, mouse; C526877:CD1D protein, human; D007378:Interleukins; D019253:Proto-Oncogene Proteins c-bcl-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018664:Interleukin-12; D007073:Immunoglobulin E; D010047:Ovalbumin; D000098546:Interleukin-21