Mycobacterial trehalose 6,6'-dimycolate preferentially induces type 1 helper T cell responses through signal transducer and activator of transcription 4 protein.
Mycobacterium tuberculosis is an intracellular pathogen of tuberculosis and its pathogenicity is related to the ability to escape killing by ingested macrophages and induce delayed-type hypersensitivity (DTH). A major component of the cell wall of M. tuberculosis is trehalose 6,6'-dimycolate (TDM), which has been implicated as a pathogenetic factor. The expression of DTH and cell-mediated immunity is dependent on the macrophage-cytokine-type 1 helper T (Th1) lymphocyte axis. Cytokines, interleukin-12 (IL-12) and interferon-gamma (IFN-gamma), play a critical role in the process and IL-12-activated signal transducer and activator of transcription (STAT) 4 is required for the development of fully functional Th1 cells. To clarify host responses to mycobacterial TDM, we have analyzed footpad reaction, histopathology and cytokine profile of experimental granulomatous lesions using STAT4-deficient mice. In the present study, we have demonstrated that mycobacterial TDM selectively induces the Th1 response through the STAT4 signaling pathway, because mice lacking STAT4 protein significantly reduced to develop DTH, hypersensitivity granulomas, and Th1 cytokine responses, when compared to BALB/c mice. These results shed light on the molecular pathogenesis of mycobacterial disease. Taken together with previous studies, TDM is a pleiotropic molecule against the host and participates in the pathogenesis.
Oiso
Ryuta
R
Department of Host Defense, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan. ryuta@med.osaka-cu.ac.jp
Fujiwara
Nagatoshi
N
Yamagami
Hirokazu
H
Maeda
Shinji
S
Matsumoto
Sohkichi
S
Nakamura
Shiro
S
Oshitani
Nobuhide
N
Matsumoto
Takayuki
T
Arakawa
Tetsuo
T
Kobayashi
Kazuo
K
D000818:Animals; D003311:Cord Factors / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005528:Foot; D006099:Granuloma; D006968:Hypersensitivity, Delayed / Q000503:physiopathology; D018664:Interleukin-12 / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000378:metabolism / Q000472:pathogenicity*; D021122:Protein Subunits / Q000378:metabolism; D050797:STAT4 Transcription Factor; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D003311:Cord Factors; D004268:DNA-Binding Proteins; D021122:Protein Subunits; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12