CD1D

CD1D is the human gene that encodes the protein CD1d, a member of the CD1 (cluster of differentiation 1) family of glycoproteins expressed on the surface of various human antigen-presenting cells. They are non-classical MHC proteins, related to the class I MHC proteins, and are involved in the presentation of lipid antigens to T cells. CD1d is the only member of the group 2 CD1 molecules.

CD1D
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4WO4, 1ZT4, 2PO6, 3HUJ, 3SDX, 3TZV, 3U0P, 3VWJ, 3VWK, 4EN3, 4LHU, 4MNG, 4MQ7, 4WW2
Identifiers
Aliases	CD1D, CD1A, R3, R3G1, CD1d molecule
External IDs	OMIM: 188410; MGI: 107674; HomoloGene: 1337; GeneCards: CD1D; OMA:CD1D - orthologs
Gene location (Human) Chr. Chromosome 1 (human) Band 1q23.1 Start 158,178,030 bp End 158,186,427 bp
Gene location (Mouse) Chr. Chromosome 3 (mouse) Band 3 F1|3 37.91 cM Start 86,903,141 bp End 86,906,748 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte granulocyte thymus spleen blood gonad right lobe of liver appendix jejunal mucosa duodenum Top expressed in white adipose tissue left lobe of liver subcutaneous adipose tissue brown adipose tissue tunica adventitia of aorta intercostal muscle body of femur lactiferous gland fossa Rostral migratory stream More reference expression data BioGPS More reference expression data
Gene ontology Molecular function beta-2-microglobulin binding lipopeptide binding histone binding endogenous lipid antigen binding lipid antigen binding exogenous lipid antigen binding cell adhesion molecule binding protein binding Cellular component cytoplasm integral component of membrane endosome endoplasmic reticulum membrane membrane integral component of plasma membrane cell surface lysosomal membrane basolateral plasma membrane lysosome endosome membrane plasma membrane endoplasmic reticulum extracellular space external side of plasma membrane Biological process immune system process T cell selection heterotypic cell-cell adhesion positive regulation of T cell proliferation detection of bacterium positive regulation of innate immune response antigen processing and presentation, exogenous lipid antigen via MHC class Ib innate immune response viral process antigen processing and presentation, endogenous lipid antigen via MHC class Ib regulation of immune response positive regulation of T cell mediated cytotoxicity immune response Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 912 12479 Ensembl ENSG00000158473 ENSMUSG00000028076 UniProt P15813 P11609 RefSeq (mRNA) NM_001766 NM_001319145 NM_001371761 NM_001371762 NM_001371763 NM_007639 NM_001379501 NM_001379502 NM_001379503 RefSeq (protein) NP_001306074 NP_001757 NP_001358690 NP_001358691 NP_001358692 NP_031665 NP_001366430 NP_001366431 NP_001366432 Location (UCSC) Chr 1: 158.18 – 158.19 Mb Chr 3: 86.9 – 86.91 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Biological significance

CD1d-presented lipid antigens activate a special class of T cells, known as natural killer T (NKT) cells, through the interaction with the T-cell receptor present on NKT membranes. When activated, NKT cells rapidly produce Th1 and Th2 cytokines, typically represented by interferon-gamma and interleukin 4 production.

Nomenclature

CD1d is also known as R3G1

Ligands

Some of the known ligands for CD1d are:

• α-galactosylceramide (α-GalCer), a compound originally derived from the marine sponge Agelas mauritanius with no physiological role but great research utility.
• α-glucuronyl- and α-galacturonyl- ceramides, a family of compounds of microbial origin which can be found, for example, on the cell wall of Sphingomonas, a ubiquitous Gram-negative bacterium. The related β-D-glucopyranosylceramide is accumulated in antigen-presenting cells after infection, where it serves to activate invariant NKTs (iNKTs), a special kind of NKT.
• iGb3, a self antigen which has been implied in iNKT selection.
• HS44, a synthetic amino cyclitolic ceramide analogue which has less contact with the TCR, activating iNKTs in a more constrained way than α-GalCer (specially in relation to Th2 cytokines production) and thus being more interesting for therapeutic use.

Tetramers

CD1d tetramers are protein constructs composed of four CD1d molecules joined together and usually fluorescently labelled, used to identify NKT cells or other CD1d-reactive cells. In particular, type I NKT cells and some type II NKT cells are stained by them. A differentiation of these two types can be obtained in human by using an antibody against the TCR Vα24 chain, which is specific of type I NKT cells.

Although they are the most widely used of CD1d oligomers, sometimes CD1d dimers (two units) or pentamers (five units) are used instead.

In obesity and type 2 diabetes

In obesity, NKT cells exhibit both an inflammatory and anti-inflammatory function. On the one hand, they release IFN-γ, but on the other hand, they reduce inflammation via the production of IL-4 and -10.

Despite the anti-inflammatory cytokines released by NKT cells, the overall effect of CD1d and NKT cells is that of mediating the inflammation caused by diet-induced obesity. Adipocyte-specific CD1d knock-out mice, when fed a high-fat diet, are protected from obesity and exhibit reduced adipose tissue inflammation.

Obesity itself also decreases the expression of CD1d, and mice fed a high-fat diet showed reduced levels of CD1d expression in adipocytes after 16 weeks. These data suggest that differentiated adipocytes could act as antigen-presenting cells for adipose iNKT cells and that reduced expression of CD1d might be associated with iNKT cells that have been dysregulated following diet-induced obesity.

Research from 2004 showed that iNKT cell counts may be reduced in diabetes type II. Transgenic non-obese mice in which CD1d molecules were overexpressed under the control of the insulin promoter within the pancreatic islets exhibited restored function of NKT cells as immunoregulatory. Diabetes was prevented in these transgenic mice.

CD1d has been shown to play an important role in metabolic biological processes, such as retinol metabolism and steroid hormone biosynthesis process activation. There is research that suggests a connection between the impaired activity of CD1d and MASLD. One study showed that feeding CD1d knock-out mice a high-fat diet impaired lipid metabolism in the liver.

Further reading

• Melián A, Beckman EM, Porcelli SA, Brenner MB (February 1996). "Antigen presentation by CD1 and MHC-encoded class I-like molecules". Current Opinion in Immunology. 8 (1): 82–88. doi:10.1016/S0952-7915(96)80109-9. PMID 8729450.
• Joyce S (March 2001). "CD1d and natural T cells: how their properties jump-start the immune system". Cellular and Molecular Life Sciences. 58 (3): 442–469. doi:10.1007/PL00000869. PMC 11337338. PMID 11315191. S2CID 29982004.
• Sköld M, Behar SM (October 2003). "Role of CD1d-restricted NKT cells in microbial immunity". Infection and Immunity. 71 (10): 5447–5455. doi:10.1128/IAI.71.10.5447-5455.2003. PMC 201095. PMID 14500461.
• Brigl M, Brenner MB (2004). "CD1: antigen presentation and T cell function". Annual Review of Immunology. 22 (1): 817–890. doi:10.1146/annurev.immunol.22.012703.104608. PMID 15032598.
• Stove V, Verhasselt B (January 2006). "Modelling thymic HIV-1 Nef effects". Current HIV Research. 4 (1): 57–64. doi:10.2174/157016206775197583. PMID 16454711.
• Brutkiewicz RR (July 2006). "CD1d ligands: the good, the bad, and the ugly". Journal of Immunology. 177 (2): 769–775. doi:10.4049/jimmunol.177.2.769. PMID 16818729.
• Blumberg RS, Terhorst C, Bleicher P, McDermott FV, Allan CH, Landau SB, et al. (October 1991). "Expression of a nonpolymorphic MHC class I-like molecule, CD1D, by human intestinal epithelial cells". Journal of Immunology. 147 (8): 2518–2524. doi:10.4049/jimmunol.147.8.2518. PMID 1717564. S2CID 33639980.
• Balk SP, Bleicher PA, Terhorst C (January 1989). "Isolation and characterization of a cDNA and gene coding for a fourth CD1 molecule". Proceedings of the National Academy of Sciences of the United States of America. 86 (1): 252–256. Bibcode:1989PNAS...86..252B. doi:10.1073/pnas.86.1.252. PMC 286442. PMID 2463622.
• Calabi F, Jarvis JM, Martin L, Milstein C (February 1989). "Two classes of CD1 genes". European Journal of Immunology. 19 (2): 285–292. doi:10.1002/eji.1830190211. PMID 2467814. S2CID 31384394.
• Yu CY, Milstein C (December 1989). "A physical map linking the five CD1 human thymocyte differentiation antigen genes". The EMBO Journal. 8 (12): 3727–3732. doi:10.1002/j.1460-2075.1989.tb08548.x. PMC 402056. PMID 2583117.
• Martin LH, Calabi F, Milstein C (December 1986). "Isolation of CD1 genes: a family of major histocompatibility complex-related differentiation antigens". Proceedings of the National Academy of Sciences of the United States of America. 83 (23): 9154–9158. Bibcode:1986PNAS...83.9154M. doi:10.1073/pnas.83.23.9154. PMC 387093. PMID 3097645.
• Balk SP, Burke S, Polischuk JE, Frantz ME, Yang L, Porcelli S, et al. (July 1994). "Beta 2-microglobulin-independent MHC class Ib molecule expressed by human intestinal epithelium". Science. 265 (5169): 259–262. Bibcode:1994Sci...265..259B. doi:10.1126/science.7517575. PMID 7517575.
• Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, et al. (November 1997). "CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides". Science. 278 (5343): 1626–1629. Bibcode:1997Sci...278.1626K. doi:10.1126/science.278.5343.1626. PMID 9374463.
• Katabami S, Matsuura A, Chen HZ, Imai K, Kikuchi K (June 1998). "Structural organization of rat CD1 typifies evolutionarily conserved CD1D class genes". Immunogenetics. 48 (1): 22–31. doi:10.1007/s002510050396. PMID 9601940. S2CID 6715203.
• Somnay-Wadgaonkar K, Nusrat A, Kim HS, Canchis WP, Balk SP, Colgan SP, et al. (March 1999). "Immunolocalization of CD1d in human intestinal epithelial cells and identification of a beta2-microglobulin-associated form". International Immunology. 11 (3): 383–392. doi:10.1093/intimm/11.3.383. PMID 10221650.
• Campbell NA, Kim HS, Blumberg RS, Mayer L (September 1999). "The nonclassical class I molecule CD1d associates with the novel CD8 ligand gp180 on intestinal epithelial cells". The Journal of Biological Chemistry. 274 (37): 26259–26265. doi:10.1074/jbc.274.37.26259. PMID 10473580.
• Han M, Hannick LI, DiBrino M, Robinson MA (August 1999). "Polymorphism of human CD1 genes". Tissue Antigens. 54 (2): 122–127. doi:10.1034/j.1399-0039.1999.540202.x. PMID 10488738.

External links

• CD1d+antigen at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human CD1A genome location and CD1A gene details page in the UCSC Genome Browser.
• Human CD1D genome location and CD1D gene details page in the UCSC Genome Browser.