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CD1d orchestrates skin cell survival and inflammation in response to UV linking the etiology of sunburn to skin cancer

ABSTRACT: Solar UV represents a ubiquitous environmental physical insult. Thus, to maintain its integrity as an effective barrier, skin must be unusually resistant to cell death. However, UV overexposure causes sunburn1,2 (necrosis and inflammation) and cells that survive harbour damaged DNA, which if not repaired or removed by apoptosis can lead to skin cancer development3-10. CD1d, a transmembrane protein identified in glycolipid antigen presentation11,12 to invariant natural killer T (NKT) cells13,14 is expressed by epithelial cells of most tissues including skin15-17, and shares close homology between humans and mice12. Since CD1d and NKT cells are implicated in regulating UV skin carcinogenesis4,18, we studied susceptibility to UV-induced sunburn in mice either lacking expression of both CD1d and NKT cells or expressing CD1d without NKT cells. Here we show that CD1d, but not NKT cells is necessary for UV to cause sunburn. CD1d causes cells to resist apoptosis in response to UV overexposure as the means to promote cell survival and directs the expression of inflammatory response genes, resulting in tissue destruction and skin inflammation. This previously unknown action of CD1d links the etiology of sunburn to skin cancer. Keywords = CD1d knockout, UV, sunburn, cancer Keywords: other

ORGANISM(S): Mus musculus

PROVIDER: GSE2436 | GEO | 2016/11/27

SECONDARY ACCESSION(S): PRJNA91901

REPOSITORIES: GEO

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Microarray screening of RNA samples from two human myeloma and two human lymphoma cell lines

Project description:This laboratory studies the T cell recognition of glycolipid antigens, including the biochemical characterization of glycolipid antigens, the cell biology of glycolipid antigen presenting machinery, the chemical synthesis of self and foreign glycolipids, and the cellular immunology that might shed light on finding glycolipid targets for adjuvant and vaccine development. In myeloid patients, the suppression of NKT cells has been reported. This suppression is mediated by endogenous glycolipid antigens presented by CD1d, a non-classic MHC molecule. Tumor B cells express CD1d molecule and preserve the capacity in presenting glycolipid antigens to NKT cells. However, the identity of the tumor glycolipid antigens remain unknown. We recently identified isoglobotrihexosylceramide (iGb3), as one endogenous ligand for human NKT cells. We have also purified iGb3 from thymuses of pediatric patients. Thus we hypothesize that iGb3 might be directly linked to the NKT suppression in myeloma patients. The processing of iGb3 requires the “assembly line” of glycosyltransferases, the glycosidases and sphingolipid activator proteins. The loading of iGb3 antigen is dependent on lipid transfer proteins such as saposins, and the more recently characterized CD1e molecule. Thus we used the Glyo-chip approach to have a systemic survey of the above enzyme and protein components. We hope to find clues to help us in understanding the glycolipid antigen presentation in tumor B cells. EXPERIMENT: We purified RNA from 2 myeloma cell lines (U226 and 8226) by the RNAqueous kit from Ambion, TX. RNA was also purified from 2 lymphoma cell lines (Daudi and RL). 4 samples were provided to Core E of Consortium of Functional Genomics for Glyco-chip version 2 array.

2011-03-02 | E-GEOD-27600 | biostudies-arrayexpress

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Project description:Microarray analysis was performed to determine the transcriptional profiles of NKT, CD1d-aGC+ Va24-, and CD4 T cells. Clones of NKT, CD1d-aGC+ Va24-, and CD4 T cells were generated using peripheral blood drawn from two healthy individuals. RNA was extracted from cells that had been either rested (18 days post-stimulation) or stimulated (3 days post-stimulation).

2011-04-22 | E-GEOD-28726 | biostudies-arrayexpress

Immunological Proteome Resource (ImmPRes): Liver derived CD4+ T cell proteomes

Project description:T cells play a critical role in liver immunity and take part both in the initiation and in the resolution of intrahepatic inflammation. The liver contains conventional CD4 T cells, and Natural Killer T (NKT) cells that express an invariant Vα14 T cell receptor that recognizes glycolipid/CD1d antigen complexes (iNKTs) and play a role in immune surveillance and immune homeostasis. ImmPRes includes a TMT based dataset characterising the proteomes of ex-vivo liver derived CD4+ T cells along with invariant NKT (iNKT) cells

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Microarray screening of RNA samples from two human myeloma and two human lymphoma cell lines

2011-03-02 | GSE27600 | GEO

NKT, CD1d-aGC+ Va24-, and CD4 T cell clones from human peripheral blood

Project description:Microarray analysis was performed to determine the transcriptional profiles of NKT, CD1d-aGC+ Va24-, and CD4 T cells.

2011-04-22 | GSE28726 | GEO

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Unveiling the heterogeneity of NKT cells in the liver through single cell RNA sequencing

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Sortase A-cleavable CD1d identifies sphingomyelins as major class of CD1d-associated lipids

Project description:CD1d is an atypical MHC class I molecule which binds endogenous and exogenous lipids and can activate natural killer T (NKT) cells through the presentation of lipid antigens. CD1d surveys different cellular compartments including the secretory and the endolysosomal pathway and broadly binds lipids through its two hydrophobic pockets. Purification of the transmembrane protein CD1d for the analysis of bound lipids is technically challenging as the use of detergents releases CD1d-bound lipids. To address these challenges, we have developed a novel approach based on Sortase A-dependent enzymatic release of CD1d at the cell surface of live mammalian cells, which allows for single step release and affinity tagging of CD1d for shotgun lipidomics. Using this system, we demonstrate that CD1d carrying the Sortase A recognition motif shows unimpaired subcellular trafficking through the secretory and endolysosomal pathway and is able to load lipids in these compartments and present them to NKT cells. Comprehensive shotgun lipidomics demonstrated that the spectrum and abundance of CD1d-associated lipids is not representative of the total cellular lipidome but rather characterized by preferential binding to long chain sphingolipids and glycerophospholipids. As such, sphingomyelin species recently identified as critical negative regulators of NKT cell activation, represented the vast majority of endogenous CD1d-associated lipids. Moreover, we observed that inhibition of endolysosomal trafficking of CD1d surprisingly did not affect the spectrum of CD1d-bound lipids, suggesting that the majority of endogenous CD1d-associated lipids load onto CD1d in the secretory rather than the endolysosomal pathway. In conclusion, we present a novel system for the analysis of CD1d-bound lipids in mammalian cells and provide new insight into the spectrum of CD1d-associated lipids, with important functional implications for NKT cell activation.

2022-06-13 | PXD034495 | panorama

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