Loss of integrin alpha(v)beta8 on dendritic cells causes autoimmunity and colitis in mice.
The cytokine transforming growth factor-beta (TGF-beta) is an important negative regulator of adaptive immunity. TGF-beta is secreted by cells as an inactive precursor that must be activated to exert biological effects, but the mechanisms that regulate TGF-beta activation and function in the immune system are poorly understood. Here we show that conditional loss of the TGF-beta-activating integrin alpha(v)beta8 on leukocytes causes severe inflammatory bowel disease and age-related autoimmunity in mice. This autoimmune phenotype is largely due to lack of alpha(v)beta8 on dendritic cells, as mice lacking alpha(v)beta8 principally on dendritic cells develop identical immunological abnormalities as mice lacking alpha(v)beta8 on all leukocytes, whereas mice lacking alpha(v)beta8 on T cells alone are phenotypically normal. We further show that dendritic cells lacking alpha(v)beta8 fail to induce regulatory T cells (T(R) cells) in vitro, an effect that depends on TGF-beta activity. Furthermore, mice lacking alpha(v)beta8 on dendritic cells have reduced proportions of T(R) cells in colonic tissue. These results suggest that alpha(v)beta8-mediated TGF-beta activation by dendritic cells is essential for preventing immune dysfunction that results in inflammatory bowel disease and autoimmunity, effects that are due, at least in part, to the ability of alpha(v)beta8 on dendritic cells to induce and/or maintain tissue T(R) cells.
Travis
Mark A
MA
Lung Biology Center, Department of Medicine, University of California San Francisco, 1550 4th Street, Room 545, San Francisco, California 94158, USA.
Reizis
Boris
B
Melton
Andrew C
AC
Masteller
Emma
E
Tang
Qizhi
Q
Proctor
John M
JM
Wang
Yanli
Y
Bernstein
Xin
X
Huang
Xiaozhu
X
Reichardt
Louis F
LF
Bluestone
Jeffrey A
JA
Sheppard
Dean
D
D000375:Aging / Q000276:immunology; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D003092:Colitis / Q000276:immunology / Q000378:metabolism*; D003106:Colon / Q000166:cytology / Q000276:immunology; D003713:Dendritic Cells / Q000378:metabolism*; D007136:Immunoglobulins / Q000097:blood; D007156:Immunologic Memory; D016023:Integrins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D051379:Mice; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D007136:Immunoglobulins; D016023:Integrins; D016212:Transforming Growth Factor beta; C403414:integrin alphavbeta8; D015847:Interleukin-4; D007371:Interferon-gamma
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