This web page was created as an assignment for an undergraduate course at Davidson College.
CD1*: Presenting Glycolipids In the Immune System
*Disclaimer: I chose to investigate CD1 because of its ability to present molecules other than peptides to the immune system. Its ability to do this greatly increases the range of recognition of T-cells. Furthermore, very little is known about such molecules at this time; this page will present some of the newest findings..
What is CD1?
CD1 is the general term for a family of molecules that are expressed on the surfaces of dendritic cells, monocytes, and some thymocytes. CD1 molecules are similar to MHC Class I molecules in that they are involved in antigen presentation (Janeway, 2001). However, there are two significant differences:
There are four human CD1 proteins: CD1A, CD1B, CD1C, and CD1D. The family genes can be separated into two groups:
|GROUP||GENES||SPECIES||DENDRITIC CELL MATURATION||PRESENTATION (Joyce, 2003)|
|Group 1||CD1A, CD1B, CD1C||Humans, nonhuman primates, and guinea pigs||Promotes DC maturation in presence of LPS and interferon-gamma||Presents both self and foreign lipid antigens to T-cells|
|Group 2||CD1D||All species studied||Promotes DC maturation ONLY in the presence of CD40 ligand||Presents predominantly self lipids to specialized natural killer T-cells|
Table 1: CD1 groups. There are two main groups of CD1 genes based on sequence homology. They can also be characterized by their resident species and their ability to promote DC maturation (Vincent, 2002).
There is a fifth isoform, CD1E, but very little evidence was presented pertaining to the function or structure of this isoform in the immune system (Gadola, 2002 and Altamirano, 2001).
CD1 antigen genes are located at human chromosome locus 1q22 - q23 and are thus not affiliated with the MHC locus located on human chromosome 6 (Converse, 2002). CD1 mRNAs are alternatively spliced to generate surface, intracellular, and secretory isoforms (Altamirano, 2001). The genes encode three extracellular domains known as heavy chains (because of their close homology to MHC Class I heavy chains). These heavy chains do complex with beta2-m in the endoplasmic reticulum (ER). Molecular chaperones calnexin and calreticulin provide chaperoning activity in vivo for CD1 (and for MHC Class I molecules). When the chaperones are blocked by glucosidase inhibitors, the CD1 molecules cannot reach the cell surface; thus, the chaperones are imperative for protein folding (Moody, 2003). It is suggested that CD1 uses a different ligand loading intracellular pathway from that used by MHC Class I. This mechanism has not been described fully; however it is known to be independent of the transporter associated with antigen processing (TAP1 and TAP2) (Altamirano, 2001). CD1D proteins produced in Drosophila cells have been found to have a bound ligand when crystallized, suggesting that CD1D at least is loaded with ligand before reaching the cell surface (Moody, 2003). There has been little other evidence of ligand binding prior to reaching the cell surface (or ligand binding at the cell surface for that matter), but because of all the other similarities to MHC Class I and Class II molecules, it is probable that ligand binding does occur intracellularly.
MHC Class II molecules go to the cell surface in vesicles which fuse with endosomes that contain peptides that the MHC Class II molecules can display. However, some MHC Class II complexes are first transported to the cell surface and then re-internalized into endosomes (Janeway, 2001). There is evidence that this is the way CD1 molecules circulate to the cell surface. Over half of CD1B and CD1D proteins follow this "recycling" pathway. Some studies have shown that isoform-specific sequences in the cytoplasmic tails of CD1 proteins interact with adaptor-protein complexes on the cytoplasmic side of the plasma membrane, and this allows the isoforms to be sorted at the cell surface.
All isoforms do associate with beta2-m, but with varying affinity. CD1B interacts very strongly and the covalently bonded molecules can withstand a pH as low as 3.0, suggesting its ability to function in late-endosomes and lysosomes because these compartments have low pHs (Moody, 2003).
CD1D is a particularly interesting isoform, as it is the only CD1 molecule that is found in both mice and humans and has the ability to select and stimulate natural killer (NK) T-cells (Brossay, 1999). Most surface CD1 isoforms containing bound hydrophobic ligand can stimulate specific T-cell receptors on the T-cell (Altamirano, 2001).
Molecular Structure of CD1
The only human CD1 isoform to be crystallized to date is that of CD1B. Click here to see chime images. There is a network of hydrophobic channels at the core which seem to be tailored perfectly for alkyl binding. This binding groove is much different from that of MHC Class I and MHC Class II molecules. Four distinct hydrophobic binding grooves are present on the surface of the molecule, and the sequential connection of three of them allows CD1B to accomodate an alkyl chain of over sixty carbon atoms. Because of the four separate channels, it is possible that more than one ligand could occupy the groove at one time (Gadola, 2002).
Drugs That Bind to CD1
I was unable to find any significant literature on drugs that bind to CD1. However, certain detergents can be incorporated into the binding groove, and any T-cell like receptor or drug that resembles this receptor may be able to bind to the CD1:hydrophobic ligand complex.
CD1D with bound ligand can be recognized by natural killer T-cells (as explained above). When the cytoplasmic targeting sequences of CD1D are mutated, then it cannot reach the plasma membrane. Certain NK T-cells can then not recognize these cells because surface CD1D is missing (Roberts, 2002). Other mutations have not allowed either ligand-binding or proper protein folding. These mutations lead to the CD1 molecule's inability to reach the cell surface, and again is therefore not expressed on the surface.
CD1's Involvement in Autoimmune Disorders?
CD1B has the ability to present not only antigenic glycolipids, but also self-gangliosides, such as GM1, to specific T cells, suggesting its involvement in autoimmune disorders such as multiple sclerosis (Gadola, 2002). There are more than 100 different types of gangliosides, which are complex glycosphingolipids located in the neuron membranes and supporting cells in the peripheral and central nervous system. CD1B is expressed in chronic-active multiple sclerosis lesions on macrophages at the lesion edges and on inflammatory cells, but not in silent multiple sclerosis lesions. These macrophages are cells that engulf myelin debris and thus may be presenting self-gangliosides (from this debris) to T-cells. Many T-cell clones specific to glycolipids have been found in these patients as well (Shamshiev, 1999).
Altamirano, M.M., Woolfson, A., Donda, A., Shamshiev, A., Briseno-Roa, L., Foster, N.W., Veprintsev, D.B., de Libero, G., Fersht, A.R., Milstein, C. 2001. "Ligand-independent assembly of recombinant human CD1 by using oxidative refolding chromatography." PNAS 98:3288-3293.
Converse, P.J. 2002. "Thymocyte antigen CD1A." OMIM. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?cmd=entry&id=188370. Accessed 16 February 2003.
Gadola, S.D., Zaccai, N.R., Harlos, K., Shepherd, D., Castro-Palomino, J.C., Ritter, G., Schmidt, R.R., Jones, E.Y., Cerundolo, V. 2002. "Structure of human CD1b with bound ligands at 2.3 A, a maze for alkyl chains." Nat Immunol 3:721-726 (abstract)
Janeway, C.A., Travers, P., Walport, M., Schlomchik, M. Immunobiology 5: The Immune System in Health and Disease. New York: Garland Publishing, 2001.
Joyce, S. and van Kaer, L. 2003. "CD1-restricted antigen presentation: an oily matter." Curr Opin Immuno. 15:95-104.
Roberts, T., Sriram, V., Spence, P., Gui, M., Hayakawa, K., Bacik, I., Bennink, J., Yewdell, J., Brutkiewicz, R. 2002. "Recycling CD1d1 molecules present endogenous antigens processed in an endocytic compartment to NKT cells." J Immunol. 168:5409-14.
Shamshiev, A., Donda, A., Carena, I., Mori, L., Kappos, L., de Libero, G. 1999. "Self glycolipids as T-cell autoantigens." Eur. J. Immunol. 29:1667-1675.
Vincent, M.S., Leslie, D.S., Gumperz, J.E., Xiong, X., Grant, E.P., Brenner, M.B. 2002. "CD1-dependent dendritic cell instruction." Nature Immun. 3:1163-1168.
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