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Abstract
BackgroundMajor histocompatibility complex (MHC) class II molecules play crucial roles in immune activation by presenting foreign peptides to antigen-specific T helper cells and thereby inducing adaptive immune responses. Although adaptive immunity is a highly effective defense system, it takes several days to become fully operational and needs to be triggered by danger-signals generated during the preceding innate immune response. Here we show that MHC class II molecules synergize with Toll-like receptor (TLR) 2 and TLR4 in inducing an innate immune response.Methodology/Principal FindingsWe found that co-expression of MHC class II molecules and TLR2 or TLR4 in human embryonic kidney (HEK) cells 293 leads to enhanced production of the anti-microbial peptide human-β-defensin (hBD) 2 after treatment with TLR2 stimulus bacterial lipoprotein (BLP) or TLR4 ligand lipopolysaccharide (LPS), respectively. Furthermore, we found that peritoneal macrophages of MHC class II knock-out mice show a decreased responsiveness to TLR2 and TLR4 stimuli compared to macrophages of wild-type mice. Finally, we show that MHC class II molecules are physically and functionally associated with TLR2 in lipid raft domains of the cell membrane.Conclusions/SignificanceThese results demonstrate that MHC class II molecules are, in addition to their central role in adaptive immunity, also implicated in generating optimal innate immune responses.
Highlights
Innate immunity mediates the first immune response to evolutionary conserved foreign patterns upon their recognition by pattern recognition receptors
To assess a potential role of Major histocompatibility complex (MHC) class II molecules in the innate immune response we compared expression of hBD-2 or TNF in HEK293 cells transfected with HLA-DR and control cells
Quantitative real-time PCR showed that TLR2 expression levels were 1.8 times higher in cells expressing only TLR2 compared to cells expressing HLA-DR and TLR2, while the HLA-DR/TLR4 or HLA-DR/TLR7 positive cells expressed more Toll-like receptor (TLR) the cells positive for only TLR4 or TLR7 (3.5 times for TLR4 and 2.8 times for TLR7) (Figure S1A)
Summary
Innate immunity mediates the first immune response to evolutionary conserved foreign patterns upon their recognition by pattern recognition receptors. TLR are the principal pattern recognition receptors They recognize conserved molecular patterns of microbes, initiate rapid anti-microbial responses protecting the host during the fist days of infection, and generate danger-signals including cytokines and co-stimulatory molecules required for activation of the adaptive immune system [1]. Major histocompatibility complex (MHC) class II molecules play crucial roles in immune activation by presenting foreign peptides to antigen-specific T helper cells and thereby inducing adaptive immune responses. Adaptive immunity is a highly effective defense system, it takes several days to become fully operational and needs to be triggered by danger-signals generated during the preceding innate immune response. We show that MHC class II molecules synergize with Toll-like receptor (TLR) 2 and TLR4 in inducing an innate immune response
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