Viral danger signals control CD1d de novo synthesis and NKT cell activation

Abstract

The nonpolymorphic CD1 molecules present lipid antigens to T cells. In myeloid DC humans express five different CD1 proteins (CD1a-e; the corresponding CD1 genes are designated CD1A-E). A role for CD1d-restricted NKT cells in the control of virus infections has been delineated from clinical observations, mouse models and viral evasion mechanisms targeting CD1d. How NKT cells are activated by virus infections is unclear. We found that human myeloid DC differentially regulate CD1 antigen presentation in response to viral danger signals. Stimulation with type I IFN, viral TLR ligands or viruses strongly enhanced the number of CD1D transcripts in human myeloid DC but diminished the abundance of CD1A, CD1B and CD1E mRNA. These changes on the transcriptional level were mirrored by altered cellular distribution and increased surface expression of CD1d. As a consequence NKT cells were activated and showed a Th1-like response. Moreover, NKT cell activation in PBMC exposed to viral danger signals was dependent on human plasmacytoid DC which produce large amounts of IFN-a. In conclusion, our data indicate that viral danger signals trigger NKT cell activation by enhancing CD1d de novo synthesis through increasing the abundance of CD1D mRNA in human myeloid DC. IntroductionThe immune system detects viruses by recognizing antigens loaded on specialized surface molecules. The highly polymorphic MHC molecules bind to diverse peptides, traffic to the cell surface, and display this information to T cells [1]. Although distantly related to MHC proteins, the nonpolymorphic CD1 proteins constitute an evolutionarily distinct family of antigenpresenting molecules [2]. Humans express five different CD1 proteins (CD1a-e; the corresponding CD1 genes are designated CD1A-E). They are further divided into group 1 (CD1a-c) and group 2, which contains CD1d as the sole member. In contrast, CD1e is not expressed on the cell surface and is an intermediate form in terms of its homology to the other CD1 molecules. Accordingly, it is regarded as a group 3 CD1 molecule [3].By trafficking through endosomal compartments, CD1 proteins pick up antigens in a similar fashion to MHC class II molecules [4]. However, instead of peptides, CD1 molecules present lipids, glycolipids or lipopeptides of either foreign or self origin [2,5]. The CD1d-restricted NKT cells can also recognize a-galactosylceramide (aGalCer), a well-studied and highly potent CD1d ligand derived from a marine sponge [6,7]. These [18,25] or improves disease outcome [12,26]. Moreover, viruses subvert antigen presentation through CD1d [27][28][29][30][31][32][33], indicating its importance in antiviral immune defense.The mechanisms leading to activation of CD1d-restricted NKT cells in humans infected with viral pathogens are unknown. However, DC will play an important role as they link the innate and adaptive antiviral immunity [34]. DC sense invading viruses by detecting conserved pathogen-associated molecular patterns through a variety of different pattern recognition receptors, e.g. TLR...

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