Role of Th1/Th17 balance regulated by T-bet in a mouse model of Mycobacterium avium complex disease.
Th1 immune responses are thought to be important in protection against intracellular pathogens. T-bet is a critical regulator for Th1 cell differentiation and Th1 cytokine production. The aim of this study was to determine the role of T-bet in host defense against Mycobacterium avium complex (MAC) infection. Wild-type mice, T-bet-deficient mice, and T-bet-overexpressing mice were infected with MAC via intratracheal inoculation. Macrophages and dendritic cells obtained from these mice were incubated with MAC. T-bet-deficient mice were highly susceptible to MAC, compared with wild-type mice and T-bet-overexpressing mice. Neutrophilic pulmonary inflammation was also enhanced in T-bet-deficient mice, but attenuated in T-bet-overexpressing mice, following MAC infection. Cytokine expression shifted toward Th1 in the lung and spleen of T-bet-overexpressing mice, but toward Th17 in T-bet-deficient mice. IFN-γ supplementation to T-bet-deficient mice reduced systemic MAC growth but did not reduce pulmonary inflammation. In contrast, neutralization of IL-17 in T-bet-deficient mice reduced pulmonary inflammation but did not affect mycobacterial growth in any organs tested. T-bet-deficient T cells tended to differentiate toward Th17 cells in vitro following exposure to MAC. Treatment with NO donor suppressed MAC-induced Th17 cell differentiation of T-bet-deficient T cells. This study identified that the fine balance between Th1 and Th17 responses is essential in defining the outcome of MAC disease. T-bet functions as a regulator for Th1/Th17 balance and is a critical determinant for host resistance to MAC infection by controlling cytokine and NO levels.
Department of Respiratory Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan;
Masashi
M
Matsuyama
Yukio
Y
Ishii
Yuichi
Y
Yageta
Shigeo
S
Ohtsuka
Satoshi
S
Ano
Yosuke
Y
Matsuno
Yuko
Y
Morishima
Keigyou
K
Yoh
Satoru
S
Takahashi
Kenji
K
Ogawa
Cory M
CM
Hogaboam
Nobuyuki
N
Hizawa
D000818:Animals; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015269:Mycobacterium avium Complex / Q000254:growth & development / Q000276:immunology; D015270:Mycobacterium avium-intracellulare Infection / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D000098815:T-bet Transcription Factor
D020381:Interleukin-17; D015850:Interleukin-6; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D009569:Nitric Oxide; D007371:Interferon-gamma