Peroxisome Proliferator-Activated Receptor γ-Regulated Cathepsin D Is Required for Lipid Antigen Presentation by Dendritic Cells

It is well established that dendritic cells (DCs) take up, process, and present lipid Ags in complex with CD1d molecules to invariant NKT cells. The lipid-activated transcription factor, peroxisome proliferator-activated receptor γ (PPARγ), has previously been shown to regulate CD1d expression in human monocyte-derived DCs, providing a link between lipid metabolism and lipid Ag presentation. We report that PPARγ regulates the expression of a lysosomal protease, cathepsin D (CatD), in human monocyte-derived DCs. Inhibition of CatD specifically reduced the expansion of invariant NKT cells and furthermore resulted in decreased maturation of saposins, a group of lipid transfer proteins required for lysosomal lipid Ag processing and loading. These results reveal a novel mechanism of lipid Ag presentation and identify CatD as a key component of this machinery and firmly place PPARγ as the transcriptional regulator linking lipid metabolism and lipid Ag processing.

[1]  R. Dwek,et al.  Activation state and intracellular trafficking contribute to the repertoire of endogenous glycosphingolipids presented by CD1d , 2010, Proceedings of the National Academy of Sciences.

[2]  E. Adams,et al.  Recognition of Lyso-Phospholipids by Human Natural Killer T Lymphocytes , 2009, PLoS biology.

[3]  L. Nagy,et al.  Nuclear receptor signalling in dendritic cells connects lipids, the genome and immune function , 2008, The EMBO journal.

[4]  Michael B. Brenner,et al.  CD1 antigen presentation: how it works , 2007, Nature Reviews Immunology.

[5]  E. Barta,et al.  PPARgamma regulates the function of human dendritic cells primarily by altering lipid metabolism. , 2007, Blood.

[6]  G. Besra,et al.  Distinct Endosomal Trafficking Requirements for Presentation of Autoantigens and Exogenous Lipids by Human CD1d Molecules1 , 2007, The Journal of Immunology.

[7]  P. Cresswell,et al.  Saposin B is the dominant saposin that facilitates lipid binding to human CD1d molecules , 2007, Proceedings of the National Academy of Sciences.

[8]  Albert Bendelac,et al.  The biology of NKT cells. , 2007, Annual review of immunology.

[9]  G. Besra,et al.  PPARγ controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells , 2006, The Journal of experimental medicine.

[10]  R. Dwek,et al.  Impaired selection of invariant natural killer T cells in diverse mouse models of glycosphingolipid lysosomal storage diseases , 2006, The Journal of experimental medicine.

[11]  G. Besra,et al.  Role of lipid trimming and CD1 groove size in cellular antigen presentation , 2006, The EMBO journal.

[12]  V. Laurent-Matha,et al.  Cathepsin D: newly discovered functions of a long-standing aspartic protease in cancer and apoptosis. , 2006, Cancer letters.

[13]  L. Van Kaer,et al.  Lipid metabolism, atherogenesis and CD1-restricted antigen presentation. , 2006, Trends in molecular medicine.

[14]  F. Sacks,et al.  Apolipoprotein-mediated pathways of lipid antigen presentation , 2005, Nature.

[15]  R. Brutkiewicz,et al.  Cell wall glycosphingolipids of Sphingomonas paucimobilis are CD1d‐specific ligands for NKT cells , 2005, European journal of immunology.

[16]  A. Tonevitsky,et al.  Bacterial infections promote T cell recognition of self-glycolipids. , 2005, Immunity.

[17]  G. Schuler,et al.  Generation of an optimized polyvalent monocyte-derived dendritic cell vaccine by transfecting defined RNAs after rather than before maturation , 2005, The Journal of Immunology.

[18]  B. Beutler,et al.  Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections , 2005, Nature.

[19]  D. Ho,et al.  Recognition of bacterial glycosphingolipids by natural killer T cells , 2005, Nature.

[20]  G. Besra,et al.  Modulation of CD1d-restricted NKT cell responses by using N-acyl variants of alpha-galactosylceramides. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[21]  R. Proia,et al.  Lysosomal Glycosphingolipid Recognition by NKT Cells , 2004, Science.

[22]  L. Csiba,et al.  Transcriptional Regulation of Human CYP27 Integrates Retinoid, Peroxisome Proliferator-Activated Receptor, and Liver X Receptor Signaling in Macrophages , 2004, Molecular and Cellular Biology.

[23]  L. Nagy,et al.  Activation of PPARgamma specifies a dendritic cell subtype capable of enhanced induction of iNKT cell expansion. , 2004, Immunity.

[24]  H. Kuipers,et al.  Transcriptional regulation of antigen presentation. , 2004, Current opinion in immunology.

[25]  P. Savage,et al.  Editing of CD1d-Bound Lipid Antigens by Endosomal Lipid Transfer Proteins , 2004, Science.

[26]  S. Kaufmann,et al.  Saposin C is required for lipid presentation by human CD1b , 2004, Nature Immunology.

[27]  P. Cresswell,et al.  Saposins facilitate CD1d-restricted presentation of an exogenous lipid antigen to T cells , 2004, Nature Immunology.

[28]  M. Kronenberg,et al.  Natural killer T cells: natural or unnatural regulators of autoimmunity? , 2003, Current opinion in immunology.

[29]  A. Rudensky,et al.  Lysosomal cysteine proteases regulate antigen presentation , 2003, Nature Reviews Immunology.

[30]  A. Rudensky,et al.  Thymocyte expression of cathepsin L is essential for NKT cell development , 2002, Nature Immunology.

[31]  Ansuman Bagchi,et al.  Printed in U.S.A. Copyright © 2002 by The Endocrine Society Gene Expression Profile of Adipocyte Differentiation and Its Regulation by Peroxisome Proliferator-Activated , 2022 .

[32]  R. Locksley,et al.  Regulation of CD1 function and NK1.1(+) T cell selection and maturation by cathepsin S. , 2001, Immunity.

[33]  M. Brenner,et al.  CD1-specific T cells in microbial immunity. , 2001, Current opinion in immunology.

[34]  A. Kulkarni,et al.  Glycolipid antigen processing for presentation by CD1d molecules. , 2001, Science.

[35]  S. Porcelli,et al.  Murine CD1d-restricted T cell recognition of cellular lipids. , 2000, Immunity.

[36]  W. Schneider-Brachert,et al.  Cathepsin D targeted by acid sphingomyelinase‐derived ceramide , 1999, The EMBO journal.

[37]  B. Peterlin,et al.  Interactions between the Class II Transactivator and CREB Binding Protein Increase Transcription of Major Histocompatibility Complex Class II Genes , 1999, Molecular and Cellular Biology.

[38]  S. Porcelli,et al.  CD1d-restricted Recognition of Synthetic Glycolipid Antigens by Human Natural Killer T Cells , 1998, The Journal of experimental medicine.

[39]  R. Evans,et al.  PPARγ Promotes Monocyte/Macrophage Differentiation and Uptake of Oxidized LDL , 1998, Cell.

[40]  S. Park,et al.  Tissue-specific recognition of mouse CD1 molecules. , 1998, Journal of immunology.

[41]  Hiroshi Sato,et al.  CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. , 1997, Science.

[42]  W. Reith,et al.  Mutation of RFXAP, a regulator of MHC class II genes, in primary MHC class II deficiency. , 1997, The New England journal of medicine.

[43]  B. Mach,et al.  Expression of MHC class II molecules in different cellular and functional compartments is controlled by differential usage of multiple promoters of the transactivator CIITA , 1997, The EMBO journal.

[44]  B. Martin,et al.  Lysosomal proteolysis of prosaposin, the precursor of saposins (sphingolipid activator proteins): its mechanism and inhibition by ganglioside. , 1997, Archives of biochemistry and biophysics.

[45]  Greg Grabowski,et al.  Proteolytic Processing Patterns of Prosaposin in Insect and Mammalian Cells* , 1996, The Journal of Biological Chemistry.

[46]  B. Spiegelman,et al.  Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor gamma. , 1995, Current opinion in genetics & development.

[47]  A. Bendelac,et al.  CD1: presenting unusual antigens to unusual T lymphocytes. , 1995, Science.

[48]  B. Troen,et al.  Regulation of cathepsin D gene expression in HL-60 cells by retinoic acid and calcitriol. , 1995, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[49]  J. Kay,et al.  Antigen processing for presentation by class II major histocompatibility complex requires cleavage by cathepsin E , 1992, European journal of immunology.

[50]  L. Van Kaer.  NKT cells: T lymphocytes with innate effector functions. , 2007, Current opinion in immunology.

[51]  Mitchell Kronenberg,et al.  Toward an understanding of NKT cell biology: progress and paradoxes. , 2005, Annual review of immunology.

[52]  R. Evans,et al.  PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation , 2001, Nature Medicine.

[53]  Millard H. Lambert,et al.  PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ∞ AND METABOLIC DISEASE , 2001 .

[54]  河野 鉄.  CD1d-restricted and TCR-mediated activation of V α14 NKT cells by glycosylceramides , 2000 .