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Systematic approach to explore molecular mechanism for TCR‐mediated LFA‐1 activation: Modulation of TCR signaling by AMP‐activated protein kinase
Author(s) -
Wang Lin,
Kim Kwangmi,
Boger Dale L.,
Sprent Jonathan,
Hwang Inkyu
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.652
Subject(s) - microbiology and biotechnology , t cell receptor , ampk , signal transduction , t cell , protein kinase a , intracellular , chemistry , vesicle , phosphorylation , pi3k/akt/mtor pathway , cell signaling , biology , immune system , biochemistry , immunology , membrane
Lymphocyte function‐associated antigen‐1(LFA‐1), whose functionality is carefully regulated by the signaling mechanism termed “inside‐out” signal, plays multiple roles in various stages of T cell immunity. Applying the finding that 2C TCR Tg T cells actively absorb the nanometric membrane vesicles expressing a cognate pMHC (L d /QL9) plus ICAM‐1 via TCR/pMHC and LFA‐1/ICAM‐1 interactions and that the intracellular signaling process is critically engaged in the vesicle absorption, we established a high throughput screening (HTS) platform to isolate chemical compounds modulating the level of vesicle absorption. Surprisingly, a class of molecules known to interfere with oxidative phosphorylation (electron transport and ATP synthesis) in mitochondria was isolated as potent inhibitors in the HTS campaign. Further studies revealed that AMP‐activated protein kinase (AMPK), whose activity increased substantially during the mitochondria inhibitor treatments, played an important role in the inhibition of the vesicle absorption, abrogating activation of PI3K/Akt signaling pathway which is acutely activated after TCR triggering. This finding provides a new insight in understanding how T cell immunity is modulated by environmental factors, which may have effect on the cellular AMPK activity. This work was supported by NIH Grant (R01AI066146).