CD1D explained

CD1D is the human gene that encodes the protein CD1d,^[1] 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.

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.^[1] 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^[2] 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.^[3] 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.^[4]
• 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.^[5]

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.^[6]

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.^[7]

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. ^[8]

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.^[9]

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.^[10]

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.^[11]

Further reading

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

Notes and References

1. Web site: P15813 (CD1D_HUMAN). Uniprot. 1 March 2013.
2. Franck RW . C-Galactosylceramide: Synthesis and Immunology . Comptes Rendus. Chimie . 15 . 1 . 46–56 . January 2012 . 22408579 . 3293403 . 10.1016/j.crci.2011.05.006 .
3. Bendelac A, Savage PB, Teyton L . The biology of NKT cells . Annual Review of Immunology . 25 . 1 . 297–336 . 2007 . 17150027 . 10.1146/annurev.immunol.25.022106.141711 .
4. Zhou D . The immunological function of iGb3 . Current Protein & Peptide Science . 7 . 4 . 325–333 . August 2006 . 16918447 . 10.2174/138920306778018007 .
5. Kerzerho J, Yu ED, Barra CM, Alari-Pahissa E, Girardi E, Harrak Y, Lauzurica P, Llebaria A, Zajonc DM, Akbari O, Castaño AR . Structural and functional characterization of a novel nonglycosidic type I NKT agonist with immunomodulatory properties . Journal of Immunology . 188 . 5 . 2254–2265 . March 2012 . 22301545 . 3288653 . 10.4049/jimmunol.1103049 .
6. Terabe M, Berzofsky JA . The role of NKT cells in tumor immunity . Advances in Cancer Research . 101 . 277–348 . 2008 . 19055947 . 2693255 . 10.1016/S0065-230X(08)00408-9 .
7. Satoh M, Iwabuchi K . Role of Natural Killer T Cells in the Development of Obesity and Insulin Resistance: Insights From Recent Progress . Frontiers in Immunology . 9 . 1314 . 2018 . 29942311 . 6004523 . 10.3389/fimmu.2018.01314 . free .
8. Satoh M, Hoshino M, Fujita K, Iizuka M, Fujii S, Clingan CS, Van Kaer L, Iwabuchi K . June 2016 . Adipocyte-specific CD1d-deficiency mitigates diet-induced obesity and insulin resistance in mice . Scientific Reports . 6 . 1 . 28473 . 2016NatSR...628473S . 10.1038/srep28473 . 4916414 . 27329323.
9. Huh JY, Park J, Kim JI, Park YJ, Lee YK, Kim JB . Deletion of CD1d in Adipocytes Aggravates Adipose Tissue Inflammation and Insulin Resistance in Obesity . Diabetes . 66 . 4 . 835–847 . April 2017 . 28082459 . 10.2337/db16-1122 .
10. Falcone M, Facciotti F, Ghidoli N, Monti P, Olivieri S, Zaccagnino L, Bonifacio E, Casorati G, Sanvito F, Sarvetnick N . Up-regulation of CD1d expression restores the immunoregulatory function of NKT cells and prevents autoimmune diabetes in nonobese diabetic mice . Journal of Immunology . 172 . 10 . 5908–5916 . May 2004 . 15128771 . 10.4049/jimmunol.172.10.5908 .
11. Zheng Q, Xue C, Gu X, Shan D, Chu Q, Wang J, Zhu H, Chen Z . Multi-Omics Characterizes the Effects and Mechanisms of CD1d in Nonalcoholic Fatty Liver Disease Development . Frontiers in Cell and Developmental Biology . 10 . 830702 . 2022-04-08 . 35465315 . 9024148 . 10.3389/fcell.2022.830702 . free .