A novel role of CD1c in regulating CD1d-mediated NKT cell recognition by competitive binding to Ig-like transcript 4.

UNLABELLED Humans express four MHC-like CD1 molecules CD1a, b, c and d that are capable of presenting a wide variety of self or foreign lipid antigens to T cells. Much progress has been made in elucidating the function of CD1d-restricted NKT cells in both innate and adaptive immune responses. However, knowledge of the other CD1 molecules is less well defined in terms of lipid presentation and immune regulation. We have previously shown that immunoglobulin-like transcript 4 (ILT4) binds to CD1d and inhibits its recognition by NKT cells. In this study, we show that CD1c can also interact specifically with ILT4 with a higher affinity than that of CD1d. Furthermore, changes in CD1c expression seem to modulate CD1d function; up-regulation of CD1c enhances NKT recognition of CD1d and down-regulation reduces CD1d recognition. We propose that CD1c can act as a sink for the inhibitory receptor ILT4: when CD1c is up-regulated, ILT4 is recruited to CD1c, thus reducing the inhibitory effect of ILT4 on CD1d recognition. Consequently, CD1c could be a potential target for modulating NKT activity. KEYWORDS NKT, CD1d, CD1c, ILT4, antigen presentation.

[1]  A. Saghatelian,et al.  The 2.5 Å structure of CD1c in complex with a mycobacterial lipid reveals an open groove ideally suited for diverse antigen presentation. , 2010, Immunity.

[2]  H. Kawamoto,et al.  Ectopically expressed PIR-B on T cells constitutively binds to MHC class I and attenuates T helper type 1 responses. , 2009, International immunology.

[3]  P. Cresswell,et al.  Natural Lipid Ligands Associated with Human CD1d Targeted to Different Subcellular Compartments 1 , 2009, The Journal of Immunology.

[4]  G. Screaton,et al.  Ig-Like Transcript 4 Inhibits Lipid Antigen Presentation through Direct CD1d Interaction1 , 2009, The Journal of Immunology.

[5]  A. McMichael,et al.  Generation and characterisation of CD1d tetramer produced by a lentiviral expression system. , 2008, Journal of immunological methods.

[6]  A. Nakamura,et al.  Cis binding between inhibitory receptors and MHC class I can regulate mast cell activation , 2007, The Journal of experimental medicine.

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

[8]  I. Wilson,et al.  Natural killer T cells recognize diacylglycerol antigens from pathogenic bacteria , 2006, Nature Immunology.

[9]  H. Achdout,et al.  The CD85J/Leukocyte Inhibitory Receptor-1 Distinguishes between Conformed and β2-Microglobulin-Free HLA-G Molecules1 , 2005, The Journal of Immunology.

[10]  A. Fersht,et al.  The crystal structure of human CD1d with and without α-galactosylceramide , 2005, Nature Immunology.

[11]  Gennaro De Libero,et al.  Recognition of lipid antigens by T cells , 2005, Nature Reviews Immunology.

[12]  D. Ho,et al.  Bacterial glycolipids and analogs as antigens for CD1d-restricted NKT cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

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

[14]  J. Trowsdale,et al.  The LILR family: modulators of innate and adaptive immune pathways in health and disease. , 2004, Tissue antigens.

[15]  Michael B Brenner,et al.  CD1: antigen presentation and T cell function. , 2004, Annual review of immunology.

[16]  P. Bjorkman,et al.  Crystal structure of HLA-A2 bound to LIR-1, a host and viral major histocompatibility complex receptor , 2003, Nature Immunology.

[17]  Kouhei Tsumoto,et al.  Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[18]  I. Wilson,et al.  Crystal structure of CD1a in complex with a sulfatide self antigen at a resolution of 2.15 Å , 2003, Nature Immunology.

[19]  P. Peters,et al.  CD1 Molecules Efficiently Present Antigen in Immature Dendritic Cells and Traffic Independently of MHC Class II During Dendritic Cell Maturation1 , 2002, The Journal of Immunology.

[20]  Gerd Ritter,et al.  Structure of human CD1b with bound ligands at 2.3 Å, a maze for alkyl chains , 2002, Nature Immunology.

[21]  R. Mehr,et al.  CD1d endosomal trafficking is independently regulated by an intrinsic CD1d-encoded tyrosine motif and by the invariant chain. , 2001, Immunity.

[22]  Michael J. Wilson,et al.  Cutting Edge: Leukocyte Receptor Complex-Encoded Immunomodulatory Receptors Show Differing Specificity for Alternative HLA-B27 Structures1 , 2001, The Journal of Immunology.

[23]  J. Trowsdale,et al.  Genetic and functional relationships between MHC and NK receptor genes. , 2001, Immunity.

[24]  J. Bell,et al.  Functional characterization of HLA‐F and binding of HLA‐F tetramers to ILT2 and ILT4 receptors , 2000, European journal of immunology.

[25]  L. Kappos,et al.  The αβ T Cell Response to Self-Glycolipids Shows a Novel Mechanism of CD1b Loading and a Requirement for Complex Oligosaccharides , 2000 .

[26]  S. Porcelli,et al.  Human Cd1b and Cd1c Isoforms Survey Different Intracellular Compartments for the Presentation of Microbial Lipid Antigens , 2000, The Journal of experimental medicine.

[27]  M. Colonna,et al.  A family of inhibitory and activating Ig-like receptors that modulate function of lymphoid and myeloid cells. , 2000, Seminars in immunology.

[28]  E. V. van Donselaar,et al.  Separate pathways for antigen presentation by CD1 molecules. , 1999, Immunity.

[29]  P. Bjorkman,et al.  The inhibitory receptor LIR-1 uses a common binding interaction to recognize class I MHC molecules and the viral homolog UL18. , 1999, Immunity.

[30]  A. McMichael,et al.  Tetrameric Complexes of Human Histocompatibility Leukocyte Antigen (HLA)-G Bind to Peripheral Blood Myelomonocytic Cells , 1999, The Journal of experimental medicine.

[31]  G. Ogg,et al.  Human myelomonocytic cells express an inhibitory receptor for classical and nonclassical MHC class I molecules. , 1998, Journal of immunology.

[32]  A. Chott,et al.  Structure and Function of the CD1 Family of MHC‐like Cell Surface Proteins , 1995, Immunological reviews.

[33]  V. Cerundolo,et al.  Harnessing invariant NKT cells in vaccination strategies , 2009, Nature Reviews Immunology.

[34]  S. Porcelli.  The CD1 family: a third lineage of antigen-presenting molecules. , 1995, Advances in immunology.