# CD1D

## Overview
The CD1D gene encodes the CD1d protein, a type I integral membrane glycoprotein that is part of the CD1 family, which is structurally related to major histocompatibility complex (MHC) class I molecules. The CD1d protein plays a pivotal role in the immune system by presenting lipid and glycolipid antigens to natural killer T (NKT) cells, thereby influencing immune responses. Unlike classical MHC molecules that present peptide antigens, CD1d specializes in the presentation of lipid-based antigens, which is facilitated by its unique structural features, including a deep hydrophobic groove. This specialization allows CD1d to activate NKT cells, which are crucial for immune surveillance and regulation, through the secretion of cytokines that modulate immune responses. The gene's expression and function are significant in various clinical contexts, including autoimmune diseases and cancers, where alterations in CD1d can impact disease progression and immune regulation (Joyce2001CD1d; Chaudhry2014Role; Gumperz2002Functionally).

## Structure
The CD1D gene encodes the CD1d protein, a member of the CD1 family of glycoproteins, which are structurally similar to MHC class I molecules. The primary structure of CD1d includes an alpha chain that noncovalently associates with beta-2 microglobulin (β2m) during assembly. The nascent alpha chain is approximately 33,000 Da and undergoes N-linked glycosylation, resulting in a mature molecular weight of 50,000-55,000 Da (Joyce2001CD1d).

The secondary structure of CD1d features α-helices and β-sheets. The α1 and α2 domains form a deep cleft, bounded by two α helices and two β sheets, which is crucial for antigen binding. The α3 domain and β2m have an immunoglobulin-like fold and interact with each other and the β sheet floor of the α1α2 superdomain (Joyce2001CD1d).

In terms of tertiary structure, CD1d has a deep hydrophobic groove that accommodates lipid antigens. This groove is narrower and more hydrophobic than those of MHC class I and II molecules, allowing CD1d to specialize in glycolipid antigen presentation (Zeng1997Crystal).

The quaternary structure of CD1d involves forming a heterodimer with β2m, similar to MHC class I molecules (Zeng1997Crystal). The CD1d protein is characterized by specific conserved and divergent features, such as invariant cysteine residues and a Pro-Xaa-Gln sequence in the α2 domain (Balk1989Isolation).

## Function
The CD1D gene encodes the CD1d molecule, a crucial component in the immune system responsible for presenting lipid and glycolipid antigens to natural killer T (NKT) cells. CD1d is a type I integral membrane protein that functions similarly to MHC class I molecules, consisting of an α chain associated with β2-microglobulin (Joyce2001CD1d). It is primarily active in the endoplasmic reticulum and on the cell surface, where it binds to lipid antigens and presents them to NKT cells (Joyce2001CD1d).

In healthy human cells, CD1d is involved in the activation of NKT cells, which play a significant role in immune surveillance and regulation. These cells can secrete cytokines such as IL-4 and IFN-γ, influencing the differentiation of CD4+ helper T lymphocytes and contributing to the immune response against infections and tumors (Joyce2001CD1d; Exley1997Requirements). CD1d's ability to present glycolipid antigens, such as α-galactosylceramide, is essential for the activation of NKT cells, which can produce both pro-inflammatory and anti-inflammatory cytokines, thereby modulating immune responses (Joyce2001CD1d; Gumperz2002Functionally).

## Clinical Significance
Alterations in the expression or function of the CD1D gene have been implicated in various diseases, particularly autoimmune disorders and cancers. In systemic lupus erythematosus (SLE), a reduction in CD1d expression on B cells is associated with increased B cell receptor signaling and inflammatory responses, contributing to disease pathogenesis (Chaudhry2014Role). CD1d deficiency in lupus-prone mice exacerbates inflammatory dermatitis and nephritis, indicating a protective role of CD1d in these conditions (Yang2004CD1d; Yang2007Examining).

In multiple myeloma, the loss of CD1d expression is linked to disease progression. This loss may result from somatic mutations or posttranslational modifications affecting CD1d trafficking, which can hinder the activation of invariant natural killer T (iNKT) cells, crucial for antitumor responses (Spanoudakis2009Regulation). Similarly, in chronic lymphocytic leukemia (CLL), higher CD1d expression correlates with poorer prognosis, suggesting its potential as a prognostic marker (Anastasiadis2013CD1d).

In autoimmune diseases like diabetes and multiple sclerosis, CD1d-restricted NKT cells play a regulatory role, and their dysfunction or reduced numbers are associated with disease development (van2004The). These findings underscore the clinical significance of CD1D in immune regulation and disease pathogenesis.

## Interactions
The CD1d molecule interacts with several proteins during its biosynthesis and maturation. In the endoplasmic reticulum (ER), CD1d associates with the chaperones calnexin and calreticulin, which are crucial for its proper folding and the formation of disulfide bonds. This interaction is glycan-dependent, as it is inhibited by glucosidase inhibitors, indicating that glucose trimming of N-linked glycans is necessary for these associations (Kang2002Calnexin). ERp57, a thiol oxidoreductase, is also involved in the formation of disulfide bonds in CD1d, interacting indirectly through calnexin or calreticulin (Kang2002Calnexin).

CD1d can form a complex with β2-microglobulin (β2m), although it can also exit the ER without β2m association. The presence of N-linked glycans, particularly glycan 2, plays a significant role in stabilizing the CD1d-β2m complex and modulating its interaction (Paduraru2006An).

The human cytomegalovirus (HCMV) US2 protein interacts with the α3 domain of CD1d in the ER, promoting the ubiquitin-dependent proteasomal degradation of the immature form of CD1d. This interaction affects invariant NKT cell activity by down-regulating it, highlighting a mechanism of immune evasion by HCMV (Han2013Human).


## References


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[2. (Chaudhry2014Role) Mohammed S. Chaudhry and Anastasios Karadimitris. Role and regulation of cd1d in normal and pathological b cells. The Journal of Immunology, 193(10):4761–4768, November 2014. URL: http://dx.doi.org/10.4049/jimmunol.1401805, doi:10.4049/jimmunol.1401805. This article has 33 citations.](https://doi.org/10.4049/jimmunol.1401805)

[3. (Yang2004CD1d) Jun‐Qi Yang, Taehoon Chun, Hongzhu Liu, Seokmann Hong, Hai Bui, Luc Van Kaer, Chyung‐Ru Wang, and Ram Raj Singh. Cd1d deficiency exacerbates inflammatory dermatitis in mrl‐lpr/lpr mice. European Journal of Immunology, 34(6):1723–1732, May 2004. URL: http://dx.doi.org/10.1002/eji.200324099, doi:10.1002/eji.200324099. This article has 53 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/eji.200324099)

[4. (Zeng1997Crystal) Z.-H. Zeng, A. R. Castaño, B. W. Segelke, E. A. Stura, P. A. Peterson, and I. A. Wilson. Crystal structure of mouse cd1: an mhc-like fold with a large hydrophobic binding groove. Science, 277(5324):339–345, July 1997. URL: http://dx.doi.org/10.1126/science.277.5324.339, doi:10.1126/science.277.5324.339. This article has 529 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1126/science.277.5324.339)

[5. (Balk1989Isolation) S P Balk, P A Bleicher, and C Terhorst. Isolation and characterization of a cdna and gene coding for a fourth cd1 molecule. Proceedings of the National Academy of Sciences, 86(1):252–256, January 1989. URL: http://dx.doi.org/10.1073/pnas.86.1.252, doi:10.1073/pnas.86.1.252. This article has 82 citations.](https://doi.org/10.1073/pnas.86.1.252)

[6. (Kang2002Calnexin) Suk-Jo Kang and Peter Cresswell. Calnexin, calreticulin, and erp57 cooperate in disulfide bond formation in human cd1d heavy chain. Journal of Biological Chemistry, 277(47):44838–44844, November 2002. URL: http://dx.doi.org/10.1074/jbc.m207831200, doi:10.1074/jbc.m207831200. This article has 97 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m207831200)

[7. (Yang2007Examining) Jun‐Qi Yang, Xiangshu Wen, Hongzhu Liu, Gbolahan Folayan, Xin Dong, Min Zhou, Luc Van Kaer, and Ram Raj Singh. Examining the role of cd1d and natural killer t cells in the development of nephritis in a genetically susceptible lupus model. Arthritis & Rheumatism, 56(4):1219–1233, March 2007. URL: http://dx.doi.org/10.1002/art.22490, doi:10.1002/art.22490. This article has 45 citations.](https://doi.org/10.1002/art.22490)

[8. (van2004The) Hans J.J van der Vliet, Johan W Molling, B.Mary E von Blomberg, Nobusuke Nishi, Wendy Kölgen, Alfons J.M van den Eertwegh, Herbert M Pinedo, Giuseppe Giaccone, and Rik J Scheper. The immunoregulatory role of cd1d-restricted natural killer t cells in disease. Clinical Immunology, 112(1):8–23, July 2004. URL: http://dx.doi.org/10.1016/j.clim.2004.03.003, doi:10.1016/j.clim.2004.03.003. This article has 90 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.clim.2004.03.003)

[9. (Han2013Human) Jihye Han, Seung Bae Rho, Jae Yeon Lee, Joonbeom Bae, Se Ho Park, Suk Jun Lee, Sang Yeol Lee, Curie Ahn, Jae Young Kim, and Taehoon Chun. Human cytomegalovirus (hcmv) us2 protein interacts with human cd1d (hcd1d) and down-regulates invariant nkt (inkt) cell activity. Molecules and Cells, 36(5):455–464, November 2013. URL: http://dx.doi.org/10.1007/s10059-013-0221-8, doi:10.1007/s10059-013-0221-8. This article has 13 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s10059-013-0221-8)

[10. (Exley1997Requirements) Mark Exley, Jorge Garcia, Steven P. Balk, and Steven Porcelli. Requirements for cd1d recognition by human invariant vα24+ cd4−cd8− t cells. The Journal of Experimental Medicine, 186(1):109–120, July 1997. URL: http://dx.doi.org/10.1084/jem.186.1.109, doi:10.1084/jem.186.1.109. This article has 452 citations.](https://doi.org/10.1084/jem.186.1.109)

[11. (Anastasiadis2013CD1d) Athanasios Anastasiadis, Ioannis Kotsianidis, Vasileios Papadopoulos, Emmanouil Spanoudakis, Dimitrios Margaritis, Anna Christoforidou, Stamatoula Gouliamtzi, and Costas Tsatalas. Cd1d expression as a prognostic marker for chronic lymphocytic leukemia. Leukemia & Lymphoma, 55(2):320–325, July 2013. URL: http://dx.doi.org/10.3109/10428194.2013.803222, doi:10.3109/10428194.2013.803222. This article has 15 citations.](https://doi.org/10.3109/10428194.2013.803222)

[12. (Paduraru2006An) Crina Paduraru, Laurentiu Spiridon, Weiming Yuan, Gabriel Bricard, Xavier Valencia, Steven A. Porcelli, Petr A. Illarionov, Gurdyal S. Besra, Stefana M. Petrescu, Andrei-Jose Petrescu, and Peter Cresswell. An n-linked glycan modulates the interaction between the cd1d heavy chain and β2-microglobulin. Journal of Biological Chemistry, 281(52):40369–40378, December 2006. URL: http://dx.doi.org/10.1074/jbc.m608518200, doi:10.1074/jbc.m608518200. This article has 25 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m608518200)

[13. (Spanoudakis2009Regulation) Emmanouil Spanoudakis, Ming Hu, Kikkeri Naresh, Evangelos Terpos, Valeria Melo, Alistair Reid, Ioannis Kotsianidis, Saad Abdalla, Amin Rahemtulla, and Anastasios Karadimitris. Regulation of multiple myeloma survival and progression by cd1d. Blood, 113(11):2498–2507, March 2009. URL: http://dx.doi.org/10.1182/blood-2008-06-161281, doi:10.1182/blood-2008-06-161281. This article has 88 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1182/blood-2008-06-161281)

[14. (Gumperz2002Functionally) Jenny E. Gumperz, Sachiko Miyake, Takashi Yamamura, and Michael B. Brenner. Functionally distinct subsets of cd1d-restricted natural killer t cells revealed by cd1d tetramer staining. The Journal of Experimental Medicine, 195(5):625–636, March 2002. URL: http://dx.doi.org/10.1084/jem.20011786, doi:10.1084/jem.20011786. This article has 620 citations.](https://doi.org/10.1084/jem.20011786)