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.
Highlights
H5N1 influenza viruses are highly pathogenic avian influenza (HPAI) virus, which infect humans and cause fatal human respiratory diseases [1, 2]
We provided the first evidence that ADAP was indispensable for autocrine Transforming growth factor β1 (TGF-β1) production and CD103 expression via the TβR-TRAF6-ADAP-TAK1-SMAD3 pathway
Compared to that of wild type cells, we observed that OVA-stimulated ADAP-/- CD8+ cytotoxic T lymphocytes (CTLs) significantly reduced TGF-β1 production at precursor levels by anti-LAP (TGF-β1) staining (7.64% vs. 24.61%) or at mRNA levels by RT-PCR analysis (Fig 1A and 1B)
Summary
H5N1 influenza viruses are highly pathogenic avian influenza (HPAI) virus, which infect humans and cause fatal human respiratory diseases [1, 2]. Compared with the influenza virus subtype H1N1, H5N1-infected patients showed unusually high serum levels of chemokines and inflammatory cytokines. The appearance of cytokine storm ( termed hypercytokinemia) is one of the most important features of H5N1 and H1N1 immunopathogenesis, mouse models deficient of cytokines IL-6 or MIP-1α show comparable mortality as influenza-challenged wild type controls [4, 6]. This might be due to the redundancy between cytokines or chemokines. Identification of other strategies to prevent cytokine storm or damage of respiratory tract is crucial and should shed new light on effective clinical anti-H5N1 or H1N1 treatment
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