Abstract
Early and strong production of IFN-I by dendritic cells is important to control vesicular stomatitis virus (VSV), however mechanisms which explain this cell-type specific innate immune activation remain to be defined. Here, using a genome wide association study (GWAS), we identified Integrin alpha-E (Itgae, CD103) as a new regulator of antiviral IFN-I production in a mouse model of vesicular stomatitis virus (VSV) infection. CD103 was specifically expressed by splenic conventional dendritic cells (cDCs) and limited IFN-I production in these cells during VSV infection. Mechanistically, CD103 suppressed AKT phosphorylation and mTOR activation in DCs. Deficiency in CD103 accelerated early IFN-I in cDCs and prevented death in VSV infected animals. In conclusion, CD103 participates in regulation of cDC specific IFN-I induction and thereby influences immune activation after VSV infection.
Highlights
Type I interferon (IFN-I) is the strongest antiviral cytokine and prevents severe outcome of virus infection [1, 2]
In contrast to plasmacytoid dendritic cells (pDCs), Conventional dendritic cells (cDCs) produce hardly any IFN-I after uptake of vesicular stomatitis virus (VSV) into TLR7 containing endosomes, and only extensive replication of VSV in cDCs leads to retinoic acid inducible gene I (RIG-I) activation and IFNI induction [37, 44, 45]
Our data indicate that expression of CD103 is one factor, which explains this difference between pDCs and cDCs
Summary
Type I interferon (IFN-I) is the strongest antiviral cytokine and prevents severe outcome of virus infection [1, 2]. Conventional dendritic cells (cDCs) are equipped with TLR7/9 and molecules of the IRF7 signaling cascade, compared to pDCs, cDCs produce reduced amounts of IFN-I upon activation of TLR7/9 [14]. During virus infection, cDCs mainly produce IFN-I after activation of RIG-I [15] One explanation for this difference between cDCs and pDCs for IFN-I production is signaling of FcεR1g and DAP12, which in cDCs inhibits IRF7 activation after TLR7/9 triggering [13]. The involvement of the PI3K-AKT pathway and mTOR signaling was shown to be a major innate immune regulator, which can regulate IFN-I induction and switches pDCs into high IFN-I producer [16,17,18]. Mechanisms underlying a potential differential AKT/mTOR activation linked to distinct abilities to produce IFN-I in cDCs have to be defined
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