Structure of mouse CD1d
CD1 (Cluster of Differentiation 1) is a family of glycoproteins involved in the presentation of antigens on the surface of specific cells to NKT cells. Amongst these CD1-presenting cells can be counted splenic dendritic cells, marginal zone B cells and CD4+CD8+ thymocytes. This family is made of two main groups: group 1 is composed of CD1a, b and c proteins and group 2 is composed of CD1d proteins[1].
Thus, the structure and function of such proteins in mice are akin to those of humans. Mice doesn’t express group 1 CD1 molecules. Instead, they have two kinds of CD1d molecules. Therefore, they have been widely used to characterize the functions of CD1d and CD1d-dependent NKT cells in many diseases.
Function
CD1d dependent lipid antigen presentation. Role in the immune system
CD1d protein is a molecule of the immune system. It is involved in presenting a lipid antigen to NKT cells. Indeed, these proteins are located on the surface of the plasma membrane of APC cells. When the recognition between the CD1d bound to its lipid ligand and the TCR of a NKT cell occurs, the lymphocyte turns out to be activated. Thus, the production of cytotoxic molecules such as Th1, Th2, interleukin-4 and INF-gamma is triggered by this activation[2][3]. Therefore, CD1d proteins are precursors of the adaptive immune reaction which are key activators of the NKT cells. As a result, a deficiency of CD1d proteins may lead to a deficiency of the NKT cells functioning and thus to autoimmune diseases and cancers.
Ligands presented by CD1d
The ligands that can be presented by CD1d to NKT or other CD1d-restricted T cells are very specific. Only a narrow set of molecules can bind its recognition site. Thus, it limits the risk of other similar molecules or binding CD1d proteins and ensures that the immune response is accurate. Among these molecules are included glycolipids from a marine sponge, bacterial glycolipids, normal endogenous glycolipids, tumor-derived phospholipids and glycolipids, and nonlipidic molecules[4].
Structure
CD1d protein is made of 2 chains[5]:
- - an (T-cell surface glycoprotein CD1d1) of 287 amino acids
- - a of 99 amino acids.
The first chain is made of two
beta-sheets and a set of 2
alpha helix. Each beta-sheet contains four antiparallel strands. The total molecular weight of the alpha chain is 33 kDa when not associated to any oligosaccharide and 55 kDa when the five oligosaccharides are associated to the chain.
The ligand binds between the two alpha-helices.
Additionally, there are two bound to the alpha chain via N-glycosylations and three types of small molecules bound to that protein[5]. CD1d molecules are structurally similar to Major Histocompatibility Complex Class I, but present lipid antigens as opposed to peptides and the cleft where the ligand can bind its protein is different between MHC molecules and CD1d molecules. Indeed, the hydrophobic cleft of CD1d has a narrow opening.The recognition between the protein and its ligand occurs at a specific spot which creates an appropriate environment for the interaction to happen. This is located at the A and F pockets in the region of the alpha helices[6].
Impact of ligand-binding
Conformational variation
NTK cells are a subset of T cells (which play a central role in the immune response) that are activated by CD1d-glycolipid complexes. α-GalCer is a potent NKT cell agonist when presented by CD1d. The stability of the CD1d-glycolipid complexes has an impact on the cytokine release (cell signaling). Conformational variations that would stabilize the F’-pocket (primary site of interaction with the T cell receptor, NKT TCR) might increase CD1d affinity for the NKT TCR[3][6].
between CD1d no ligand and structure of bovine CD1d with bound C12-di-sulfatide.
CD1d affinity
CD1d proteins lipid recognition is based on the interaction of the protein with its ligand. Nevertheless, the recognition relies on two recognitions. The first one is the recognition of the head of the lipid and the second one is the recognition of the length of the molecule. Because there are more than one condition to fill in order to interact with CD1d proteins, the affinity for a lipid depends itself on a plurality of parameters which modulates it[3][6][7].
Applications
Immunotherapeutic tool
The presentation of many of ligands can have immunopotentiating effects, such as serving as an adjuvant against malaria or resulting in a more rapid clearance of certain virus infections. They can also be protective in autoimmune diseases or cancer[3][4][8].
The presence of high amount of CD1d proteins on the cell surface of NKT cells gives rise to a novel type of NKT cells. This larger amount of CD1d proteins allows the Cd1d high NKT cells to bind more alpha-galactosylceramide molecules and therefore to can produce greater levels of interleukin-4 and INF-gamma molecules leading to possible therapeutical effects[3].
NKT cells marker
CD1 molecules can also be used as NKT cell markers. Indeed, a CD1 molecule can be engineered to become fluorescent by binding a fluorescent-potent molecule to it. When the engineered complex interacts with a NKT cell, the fluorescent signal is emitted and therefore the NKT cells can be spotted[9].
See Also
References
- ↑ Jullien, D.; Afanassieff, M.; Claudy, A.; Nicolas, J.; Kaiserlian, D. CD1 : une nouvelle famille de molécules présentatrices d’antigènes aux caractéristiques singulières. Med Sci (Paris) 1999, 15 (1), 7. https://doi.org/10.4267/10608/1190.
- ↑ Joyce, S. CD1d and Natural T Cells: How Their Properties Jump-Start the Immune System. CMLS, Cell. Mol. Life Sci. 2001, 58 (3), 442–469. https://doi.org/10.1007/PL00000869.
- ↑ 3.0 3.1 3.2 3.3 3.4 Rossjohn, J., Pellicci, D. G., Patel, O., Gapin, L., & Godfrey, D. I. (2012). Recognition of CD1d-restricted antigens by natural killer T cells. Nature reviews. Immunology, 12(12), 845–857. https://doi.org/10.1038/nri3328.
- ↑ 4.0 4.1 Brutkiewicz, R. R. CD1d Ligands: The Good, the Bad, and the Ugly. The Journal of Immunology 2006, 177 (2), 769–775. https://doi.org/10.4049/jimmunol.177.2.769.
- ↑ 5.0 5.1 Information, N. C. for B.; Pike, U. S. N. L. of M. R.; BethesdaMD; 20894USA. 3GMQ: Structure of mouse CD1d expressed in SF9 cells, no ligand added https://www.ncbi.nlm.nih.gov/Structure/pdb/3GMQ (accessed Dec 5, 2020).
- ↑ 6.0 6.1 6.2 Schiefner, A.; Fujio, M.; Wu, D.; Wong, C.-H.; Wilson, I. A. Structural Evaluation of Potent NKT-Cell Agonists: Implications for Design of Novel Stimulatory Ligands. J Mol Biol 2009, 394 (1), 71–82. https://doi.org/10.1016/j.jmb.2009.08.061
- ↑ McCarthy, C.; Shepherd, D.; Fleire, S.; Stronge, V. S.; Koch, M.; Illarionov, P. A.; Bossi, G.; Salio, M.; Denkberg, G.; Reddington, F.; Tarlton, A.; Reddy, B. G.; Schmidt, R. R.; Reiter, Y.; Griffiths, G. M.; van der Merwe, P. A.; Besra, G. S.; Jones, E. Y.; Batista, F. D.; Cerundolo, V. The Length of Lipids Bound to Human CD1d Molecules Modulates the Affinity of NKT Cell TCR and the Threshold of NKT Cell Activation. J Exp Med 2007, 204 (5), 1131–1144. https://doi.org/10.1084/jem.20062342.
- ↑ Sköld, M.; Behar, S. M. Role of CD1d-Restricted NKT Cells in Microbial Immunity. Infect Immun 2003, 71 (10), 5447–5455. https://doi.org/10.1128/IAI.71.10.5447-5455.2003.
- ↑ Benlagha, K., Weiss, A., Beavis, A., Teyton, L., & Bendelac, A. (2000). In vivo identification of glycolipid antigen-specific T cells using fluorescent CD1d tetramers. The Journal of experimental medicine, 191(11), 1895–1903. https://doi.org/10.1084/jem.191.11.1895
