Abstract
Highly pathogenic avian influenza virus (HPAI, such as H5N1) infection causes severe cytokine storm and fatal respiratory immunopathogenesis in human and animal. Although TGF-β1 and the integrin CD103 in CD8+ T cells play protective roles in H5N1 virus infection, it is not fully understood which key signaling proteins control the TGF-β1-integrin crosstalk in CD8+ T cells to protect from H5N1 virus infection. This study showed that ADAP (Adhesion and Degranulation-promoting Adapter Protein) formed a complex with TRAF6 and TAK1 in CD8+ T cells, and activated SMAD3 to increase autocrine TGF-β1 production. Further, TGF-β1 induced CD103 expression via an ADAP-, TRAF6- and SMAD3-dependent manner. In response to influenza virus infection (i.e. H5N1 or H1N1), lung infiltrating ADAP-/- CD8+ T cells significantly reduced the expression levels of TGF-β1, CD103 and VLA-1. ADAP-/- mice as well as Rag1-/- mice receiving ADAP-/- T cells enhanced mortality with significant higher levels of inflammatory cytokines and chemokines in lungs. Together, we have demonstrated that ADAP regulates the positive feedback loop of TGF-β1 production and TGF-β1-induced CD103 expression in CD8+ T cells via the TβRI-TRAF6-TAK1-SMAD3 pathway and protects from influenza virus infection. It is critical to further explore whether the SNP polymorphisms located in human ADAP gene are associated with disease susceptibility in response to influenza virus infection.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Antigens, CD / metabolism*
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism*
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CD8-Positive T-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / virology
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Cell Line
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Crosses, Genetic
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Humans
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Immunity, Mucosal
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Influenza A Virus, H1N1 Subtype / immunology*
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Influenza A Virus, H5N1 Subtype / immunology*
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Influenza, Human / immunology
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Influenza, Human / metabolism
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Influenza, Human / pathology
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Influenza, Human / virology
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Integrin alpha Chains / metabolism*
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Lung / immunology
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Lung / metabolism
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Lung / pathology
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Lung / virology
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Protein Serine-Threonine Kinases / metabolism
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / agonists
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Receptors, Transforming Growth Factor beta / metabolism
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Recombinant Proteins / metabolism
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Respiratory Mucosa / immunology
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Respiratory Mucosa / metabolism
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Respiratory Mucosa / pathology
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Respiratory Mucosa / virology
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Signal Transduction
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Specific Pathogen-Free Organisms
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Transforming Growth Factor beta1 / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, CD
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FYB1 protein, human
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Fyb protein, mouse
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Integrin alpha Chains
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Receptors, Transforming Growth Factor beta
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Recombinant Proteins
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Transforming Growth Factor beta1
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alpha E integrins
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
Grants and funding
This work was funded by: The Ministry of Science and Technology of China, 2012CB910800, HW; National Natural Science Foundation of China, (31422018, 31070778 & 31370859), HW; WIV “One-Three-Five” Strategic Programs, BW; Shanghai Pujiang program, 11PJ1410700, HW and the Hundred Talents Program of the Chinese Academy of Sciences, HW. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.