HGNC Approved Gene Symbol: CD1D
Cytogenetic location: 1q23.1 Genomic coordinates (GRCh38): 1:158,178,030-158,186,427 (from NCBI)
CD1D is the sole group-2 member of the CD1 family of major histocompatibility (MHC)-like glycoproteins. See CD1A (188370) for background on CD1 molecules.
Balk et al. (1994) found that CD1D, which is a ligand for CD8(+) T cells, is expressed on the surface of human intestinal epithelial cells (IECs) as a 37-kD protein that is beta-2-microglobulin (B2M; 109700)-independent, with no N-linked carbohydrate. Transfection into a B2M-negative cell line confirmed that CD1D can be expressed at the cell surface in the absence of beta-2-microglobulin. The findings indicated that IECs use a specialized pathway for CD1D synthesis and that a B2M-independent class Ib protein may be the normal ligand for some intestinal T cells.
In a review of CD1 lipid antigen presentation, Park and Bendelac (2000) stated that the main T cell subset associated with CD1D is the natural killer (NK) T cell, which expresses a T-cell receptor (TCR) made of an invariant TCRA (see 186880) associated with diverse V-beta-11 (see 186930) chains. This TCR recognizes a conserved family of glycolipids, alpha-galactosylceramide, a form of which is predicted to exist in mammalian hosts. These NK T cells are active in autoimmune diabetes (see 605026 and 222100), tumor rejection, and some microbial infections.
Jayawardena-Wolf et al. (2001) described 2 different pathways of Cd1d trafficking to endosomal compartments in mouse cells. A tyrosine-based motif governs recycling between the plasma membrane and the endosome, while Cd1d associates, like major histocompatibility complex class II antigens, with the invariant chain, or Ii (CD74; 142790), in the endoplasmic reticulum. Both pathways enhance antigen presentation to Cd1d-restricted natural killer T cells.
NKT cells express both the alpha-beta T cell receptor and inhibitory MHC-specific NK receptors (NKR; e.g., LY49, 604274). Unlike autoreactive T cells, the rare autoreactive NKT cells are not deleted in the thymus but are positively selected upon recognition of CD1D (with, presumably, an endogenous ligand) expressed by CD4+CD8+ double-positive cortical thymocytes. Deletion of the NKR, or the absence of MHC molecules on target cells, abolishes control of autoreactivity. Using fluorescent CD1D tetramers loaded with the synthetic lipid alpha-galactosylceramide, which uniformly stain all NKT cells expressing the V-alpha-14-J-alpha-18/V-beta-8 TCR, Benlagha et al. (2002) identified, in 2-week-old mice, predominantly CD44-low NK1.1- thymocytes, which mature into CD44-high NK1.1- and then CD44-high NK1.1+ cells. Other NKR such as LY49 are also expressed late in NKT cells. Maturation to the NKR+ stages corresponded with a conversion from production of TH2- (e.g., IL4, 147780) to TH1- (e.g., IFNG, 147570) type cytokines, with an intermediary phase of mixed IL4/IFNG production. Benlagha et al. (2002) suggested that the thymic and postthymic developmental pathways expand autoreactive cells and differentiate them into regulatory cells. In a commentary, MacDonald (2002) proposed a model for the intrathymic development and export of NKT cells.
Pellicci et al. (2002) used a similar strategy and confirmed the thymus-dependence of NKT cells by showing that these cells are not produced in athymic nude mice. They also demonstrated that NKR- cells give rise to NKR+ cells but not vice versa. CD4+ thymocytes may differentiate to either CD4+ or CD4- NKR+ cells.
Vincent et al. (2002) showed that group-1 (i.e., CD1A, CD1B, and CD1C) foreign antigen-nonspecific CD1-restricted T-cell clones could promote dendritic cell (DC) maturation in the presence of lipopolysaccharide and IFNG, whereas group-2 (i.e., CD1D)-restricted T cells failed to induce interleukin-12 p70 (IL12; see 161561) production and DC maturation except in the presence of CD40 ligand (CD40LG; 300386). On the other hand, the CD1D-restricted T-cell clones were more efficient producers of IL10 (124092).
Kang and Cresswell (2004) transduced fibroblast lines from prosaposin (PSAP; 176801)-deficient mice with human CD1D and PSAP and showed that saposins were not required for autorecognition of CD1D by natural killer T cells, but were indispensable for binding of an exogenous lipid antigen, alpha-galactosylceramide, to CD1D in the endocytic pathway. They proposed that saposins mobilize monomeric lipids from lysosomal membranes and facilitate their association with CD1D.
Zhou et al. (2004) found that mouse and human NKT cells recognized the lysosomal glycosphingolipid isoglobotriaosylceramide (iGb3). Impaired generation of lysosomal iGb3 in mice lacking Cd1d resulted in severe NKT cell deficiency, suggesting that iGb3 mediates development of NKT cells in mouse. Zhou et al. (2004) proposed that expression of iGb3 in peripheral tissues may be involved in controlling NKT cell responses to infections and malignancy and in autoimmunity.
In mice, Olszak et al. (2014) showed that while bone marrow-derived Cd1d signals contribute to NKT cell-mediated intestinal inflammation, engagement of epithelial Cd1d elicits protective effects through the activation of Stat3 (102582) and Stat3-dependent transcription of Il10, Hsp110 (610703), and Cd1d itself. All of these epithelial elements are critically involved in controlling CD1D-mediated intestinal inflammation. This was demonstrated by severe NKT cell-mediated colitis upon intestinal epithelial cell-specific deletion of IL10, CD1D, and its critical regulator microsomal triglyceride transfer protein (MTP; 157147), as well as deletion of HSP110 in the radioresistant compartment. Olszak et al. (2014) concluded that these studies uncovered a novel pathway of intestinal epithelial cell-dependent regulation of mucosal homeostasis as well as highlighted a critical role for IL10 in the intestinal epithelium, with broad implications for diseases such as inflammatory bowel disease.
Murine and human CD1D exhibit 70% identity to each other. Park and Bendelac (2000) noted that the crystal structure of murine CD1D (see Zeng et al., 1997), which has a deep ligand-binding groove made of 2 large electrostatically neutral pockets lined with clustered hydrophobic residues, appears to suggest a way in which CD1, which complexes with B2M molecules, binds lipids. Park and Bendelac (2000) also observed that the stable lipid binding might occur in the secretory pathway, at the cell surface, or only after internalization in an acidified compartment. The intracellular location of CD1D is the late endosome or lysosome. Access to the endocytic pathway is regulated by a tyrosine-based motif in the cytoplasmic tail of CD1 that differs among CD1B (188360), CD1C (188340), and CD1D.
Alpha-galactosylceramide (alpha-GalCer), a marine sponge glycosphingolipid (GSL), and some disaccharide GSLs can be presented by CD1D in vitro without antigen-presenting cells (APCs) to NK T cells, which respond by producing interleukin-2 (IL2; 147680). Prigozy et al. (2001), however, found that sugars linked at the 2-prime or 3-prime position of the galactose must be removed by APCs in order to stimulate NK T cells. Immunofluorescence microscopy, supported by functional assays, showed that intact CD1D, but not cytoplasmic tail-deleted mutants lacking the endosomal-targeting motif, localized to lysosomes as well as to the plasma membrane, and could present 2-prime-linked alpha-GalGalCer to NK T cells. Such 2-prime-linked alpha-GalGalCer antigen presentation could be blocked by lysosomotropic inhibitors and specifically by an inhibitor of alpha-galactosidase A (GLA; 300644). Alternatively, alpha-galactosidase A-mediated removal of the terminal galactose permitted the presentation of the 2-prime-linked alpha-GalGalCer to NK T cells in the absence APCs. Prigozy et al. (2001) also found that splenic APCs from alpha-galactosidase A-deficient mice, a model of Fabry disease (301500), could present alpha-GalCer or 6-prime-linked alpha-GalGalCer but not 2-prime-linked alpha-GalGalCer to NK T-cell lines. Prigozy et al. (2001) concluded that the demonstration of a carbohydrate antigen-processing pathway could extend the range of antigens that are presented by CD1 molecules.
Borg et al. (2007) described the structure to 3.2-angstrom resolution of a human NKT TCR in complex with CD1D bound to the potent NKT-cell agonist alpha-galactosylceramide, the archetypal CD1D-restricted glycolipid. In contrast to TCR-peptide-antigen-MHC complexes, the NKT TCR docked parallel to and at the extreme end of the CD1D-binding cleft, which enables a lock-and-key type interaction with the lipid antigen. The structure provided a basis for the interaction between the highly conserved NKT TCR alpha-chain and the CD1D antigen complex that is typified in innate immunity, and also indicated how variability of the NKT TCR beta-chain can impact recognition of other CD1D antigen complexes. Borg et al. (2007) concluded that their findings provided direct insight into how a T-cell receptor recognizes a lipid antigen-presenting molecule of the immune system.
See 188370 for information on mapping of the CD1D gene to 1q22-q23. Bradbury et al. (1991) showed that the homologous mouse gene, Cd1d, is on chromosome 3.
Quantitative and qualitative defects in CD1-restricted natural killer T cells are found in autoimmune-prone strains of mice, including the nonobese diabetic (NOD) mouse. These defects appear to be associated with the emergence of spontaneous autoimmunity. Shi et al. (2001) demonstrated that CD1d-null NOD transgenic mice have accelerated onset and increased incidence of diabetes when compared with CD1d +/- and CD1d +/+ littermates. The pancreata of CD1d-null mice harbored significantly higher numbers of activated memory T cells expressing the chemokine receptor CCR4 (604836). Notably, the presence of these T cells was associated with immunohistochemical evidence of increased destructive insulitis. Thus, CD1d-restricted T cells are critically important for regulation of the spontaneous disease process in NOD mice.
Cathepsins S (CTSS; 116845) and L (CTSL; 116880) play prominent roles in the degradation of the invariant chain (Ii). In I-A(b) class II mice lacking the Ctss gene, failure to degrade Ii resulted in the accumulation of a class II-associated, 10-kD Ii fragment within endosomes, disrupting class II trafficking, peptide complex formation, and class II-restricted antigen presentation (Driessen et al., 1999). Riese et al. (2001) showed that I-A(b) class II haplotype mice lacking the Ctss gene had impaired NK1.1-positive T-cell selection and function. There were no overt defects in Cd4 (186940)-positive and Cd8 (see 186910)-positive T-cell populations. In Ctss -/- mice, thymic dendritic cells had defective presentation of the Cd1d-restricted antigen, the marine sponge glycosphingolipid alpha-galactosylceramide. Cd1d colocalized with Ii fragments and accumulated within endocytic dendritic cell compartments, impairing Cd1d trafficking. This dysfunction did not occur, however, in Ctss -/- mice of the I-A(k) class II haplotype. Riese et al. (2001) concluded that Cd1d function is critically linked to the processing of Ii, revealing that MHC class II haplotype and Ctss activity are regulators of NK T cells.
Nieuwenhuis et al. (2002) showed that clearance of intranasally applied Pseudomonas aeruginosa is impaired in the lungs of CD1d-deficient mice as well as in T cell-deficient mice. Failure to clear the bacteria was associated with a markedly reduced influx of neutrophils in the bronchoalveolar lavage fluid in the early stages of the infection, which was thought to result from impaired production of chemokines such as Mip2 (139110) by alveolar macrophages. Prior administration of alpha-galactosylceramide to wildtype mice induced almost complete eradication of P. aeruginosa from their lungs, indicating that activation of CD1d-restricted T cells by alpha-galactosylceramide is critical in host defense against these bacteria. Sequential radiologic, macroscopic pathology, and histopathologic analyses confirmed early enhanced inflammation and resolution of inflammation and bacterial phagocytosis by alveolar macrophages in the alpha-galactosylceramide-treated mice, whereas control mice exhibited higher numbers of bacteria, lung hemorrhage, and swelling. Flow cytometric analysis demonstrated that the macrophage activation in alpha-galactosylceramide-treated mice was associated with increased numbers of Ifng (147570)-producing NKT cells. Nieuwenhuis et al. (2002) concluded that activation of CD1d-restricted T cells is crucial in regulating the antimicrobial immune functions of macrophages at the lung mucosal surface and suggested that this activity may help in preventing colonization in diseases such as cystic fibrosis (219700) and in patients undergoing chemotherapy.
Honey et al. (2002) found that mice lacking Ctsl lack the predominant V-alpha-14+ subset of regulatory natural killer T (NKT) cells, whereas the small subset expressing the TCRA (see 186880) chain V-alpha-3.2+ develop without impairment. Flow cytometric analysis and confocal and immunoelectron microscopy demonstrated that Cd1d cell surface expression and intracellular localization are normal in Ctsl-deficient thymocytes, as is the structure and number of lysosomes. The authors concluded that Ctsl is a critical regulator of Cd1d presentation of endogenous V-alpha-14+ NKT ligands.
Zhou et al. (2004) reported that mice deficient in prosaposin (176801), the precursor to a family of endosomal lipid transfer proteins, exhibit specific defects in CD1D-mediated antigen presentation and lack V-alpha-14 NKT cells. In vitro, saposins extracted monomeric lipids from membranes and from CD1, thereby promoting the loading as well as the editing of lipids on CD1. Transient complexes between CD1, lipid, and lipid transfer protein suggested a 'tug-of-war' model in which lipid exchange between CD1 and lipid transfer proteins is on the basis of their respective affinities for lipids. The authors concluded that lipid transfer proteins constitute a theretofore unknown link between lipid metabolism and immunity and are likely to exert a profound influence on the repertoire of self, tumor, and microbial lipid antigens.
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