CD1D is the humangene that encodes the proteinCD1d,[5] 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.
α-galactosylceramide (α-GalCer), a compound originally derived from the marine sponge Agelas mauritanius[6] with no physiological role but great research utility.
iGb3, a self antigen which has been implied in iNKT selection.[8]
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.[9]
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.[10]
Although they are the most widely used of CD1d oligomers, sometimes CD1d dimers (two units) or pentamers (five units) are used instead.[10]
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.[11]
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. [12]
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.[13]
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.[14]
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.[15]
^Huh JY, Park J, Kim JI, Park YJ, Lee YK, Kim JB (April 2017). "Deletion of CD1d in Adipocytes Aggravates Adipose Tissue Inflammation and Insulin Resistance in Obesity". Diabetes. 66 (4): 835–847. doi:10.2337/db16-1122. PMID28082459.
^Falcone M, Facciotti F, Ghidoli N, Monti P, Olivieri S, Zaccagnino L, et al. (May 2004). "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. doi:10.4049/jimmunol.172.10.5908. PMID15128771.
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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. PMID9374463.
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. PMID9601940. S2CID6715203.
