The Immune Adaptor ADAP Regulates Reciprocal TGF-β1-Integrin Crosstalk to Protect from Influenza Virus Infection

Chunyang Li, Shaozhuo Jiao, Guojun Wang, Yunzhen Gao, Chang Liu, Xijun He, Chi Zhang, Jun Xiao, Weiyun Li, Guoquan Zhang, Bin Wei, Hualan Chen, Hongyan Wang

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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.

Original languageEnglish
Article numbere1004824
JournalPLoS Pathogens
Volume11
Issue number4
DOIs
StatePublished - 1 Apr 2015
Externally publishedYes

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