Invariant NKT (iNKT) cells have the unique ability to shape immunity during antitumor immune responses and other forms of sterile and nonsterile inflammation. Recent studies have highlighted a variety of classes of endogenous and pathogen-derived lipid antigens that can trigger iNKT cell activation under sterile and nonsterile conditions. However, the context and mechanisms that drive the presentation of self-lipid antigens in sterile inflammation remain unclear. Here we report that endoplasmic reticulum (ER)-stressed myeloid cells, via signaling events modulated by the protein kinase RNA-like ER kinase (PERK) pathway, increase CD1d-mediated presentation of immunogenic endogenous lipid species, which results in enhanced iNKT cell activation both in vitro and in vivo. In addition, we demonstrate that actin cytoskeletal reorganization during ER stress results in an altered distribution of CD1d on the cell surface, which contributes to enhanced iNKT cell activation. These results define a previously unidentified mechanism that controls iNKT cell activation during sterile inflammation.
Proc natl acad sci u s a
23671 - 23681
CD1d, ER stress, NKT, cancer, Animals, Antigen Presentation, Antigen-Presenting Cells, Antigens, CD1d, Autoantigens, Carcinoma, Lewis Lung, Cell Line, Tumor, Coculture Techniques, Cytoskeleton, Dendritic Cells, Endoplasmic Reticulum Stress, Endosomes, Glycosphingolipids, Humans, Interleukin-2 Receptor alpha Subunit, Lipids, Lymphocyte Activation, Lysosomes, Mice, Mice, Inbred C57BL, Natural Killer T-Cells, THP-1 Cells, Thapsigargin, Unfolded Protein Response, eIF-2 Kinase