CD22

From CFGparadigms

CD22 is predominantly expressed on B cells and is well documented as a regulator of B cell receptor (BCR) signaling^[1]. It is one of four siglecs that are highly conserved among mammals. This paradigm is unique among the siglecs in that the cytoplasmic domain has six conserved tyrosine motifs, including three immunoreceptor tyrosine inhibitory motifs (ITIM), one ITIM-like motif, and a growth factor receptor bound protein2 (GRB2) motif. These tyrosine motifs are involved in regulation of BCR signaling and also mediate its constitutive clathrin mediated endocytosis, an activity believed to be tied to its regulation of cell signaling. The preferred glycan ligand of CD22 differs significantly in humans and mice^[1][2][3]. While both recognize the sequence Siaα-2-6Galβ-1-4GlcNAc expressed abundantly on B cells, murine CD22 prefers Neu5Gc (not found in humans) over Neu5Ac, while human CD22 exhibits highest affinity for sulfated sialoside, Neu5Acα-2-6Galβ-1-4[6S]GlcNAc, demonstrating significant evolution of ligand specificity with conservation of function. Although CD22 recognizes ligands on the same cell in cis, it also binds to ligands in trans if expressed on adjacent contacting cells. A major area of investigation is to understand the relative roles of cis and trans ligands in CD22 function.

Contents 1 CFG Participating Investigators contributing to the understanding of this paradigm 2 Progress toward understanding this GBP paradigm 2.1 Carbohydrate ligands 2.2 Cellular expression of GBP and ligands 2.3 Biosynthesis of ligands 2.4 Structure 2.5 Biological roles of GBP-ligand interaction 3 CFG resources used in investigations 3.1 Glycan profiling 3.2 Glycogene microarray 3.3 Knockout mouse lines 3.4 Glycan array 4 Related GBPs 5 References 6 Acknowledgements

CFG Participating Investigators contributing to the understanding of this paradigm

CFG Participating Investigators (PIs) have made major contributions to the understanding of the biology of human and murine CD22. These include: Nicolai Bovin, Paul Crocker, Jamey Marth, David Nemazee, Lars Nitschke, Jim Paulson, Ajit Varki

Progress toward understanding this GBP paradigm

This section documents what is currently known about CD22, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information can be found in the GBP Molecule Page for human and mouse CD22 (aka Siglec-2) in the CFG database.

Carbohydrate ligands

Although CD22 is highly conserved throughout mammalian species, murine and human CD22 are known to exhibit significant differences in their specificities that appear to have evolved to compensate for changes in the glycan ligands expressed on B cells. While both bind Siaα2-6Gal terminated glycans, murine CD22 prefers NeuGc (NeuGcα2-6Galβ1-4GlcNAc), which is not found in humans. In contrast, human human CD22 recognizes NeuAc and NeuGc with equal affinity. In addition, however, human CD22 exhibits highest affinity for a ligand with sulfate at the 6 position of GlcNAc (NeuAcα2-6Galβ1-4[6S]GlcNAc).^[1][2] 9-O-acetylation of sialic acid abrogates binding of CD22, which is thought to regulate the binding of cis ligands on B cells.

Cellular expression of GBP and ligands

CD22 is primarily expressed on mature B cells and to a lesser extent on memory B cells. However, it is not expressed on pre-B cells and differentiated plasma cells. Like many siglecs, CD22 interacts with endogenous ligands on B cells in cis, and on other cells, such as T cells and bone marrow vessel endothelial cells in trans. Although cis ligands of tend to mask the CD22 binding site, CD22 is able to interact with trans ligands on contacting cells (B cells and T cells), and to bind to synthetic multivalent ligands that have sufficient avidity.

Biosynthesis of ligands

The ligands of CD22 are predominately the product of a single sialyltransferase, ST6Gal I. Mice deficient in ST6Gal I express no ligands on B cells resulting in an immuno-deficient phenotype.

Structure

Although the crystal structure of CD22 has not yet been elucidated, structures of other siglecs, including sialoadhesin, siglec-5 and siglec-7 have shed insights into the nature of the ligand binding site of CD22.^[1]

Biological roles of GBP-ligand interaction

CFG resources used in investigations

The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for CD22.

Glycan profiling

Both murine and human CD22 recognize the sequence Siaα2-6Galβ1-4GlcNAc expressed abundantly on B cells, which have been subjected to glycan profiling by the CFG.

Glycogene microarray

The CFG glycogene microarray has been used to show that ST6Gal I is downregulated 'on T cells upon activation suggesting that B cell trans ligands are reduced on activated T cells. Probes for mouse and human CD22 have been included on all four versions of the CFG glycogene array.

Knockout mouse lines

Mice deficient in CD22 and the sialyltransferase, ST6Gal I, responsible for synthesis of its ligands (ST6Gal I) distributed by the CFG have been instrumental in understanding the biology of CD22.

Glycan array

The CFG's glycan array was instrumental in identification of the high affinity ligands of CD22 as sialylated-sulfated glycans.^[2][3]

Related GBPs

This paradigm is unique among the siglecs in that the cytoplasmic domain has six conserved tyrosine motifs, including three immunoreceptor tyrosine inhibitory motifs (ITIM), one ITIM-like motif, and a growth factor receptor bound protein2 (GRB2) motif. However, other members of the homologous siglec family have contributed to an understanding of the glycan binding site of CD22, and general principles governing the interaction of CD22 with cis and trans ligands.

References

1. ↑ ^{1.0 1.1 1.2 1.3} Crocker PR, Paulson JC, Varki A. Siglecs and their roles in the immune system. Nat Rev Immunol 2007 Apr;7(4):255-66. Review.
2. ↑ ^{2.0 2.1 2.2} Kimura N, Ohmori K, Miyazaki K, Izawa M, Matsuzaki Y, Yasuda Y, Takematsu H, Kozutsumi Y, Moriyama A, Kannagi R. Human B-lymphocytes express alpha2-6-sialylated 6-sulfo-N-acetyllactosamine serving as a preferred ligand for CD22/Siglec-2. J Biol Chem. 2007 Nov 2;282(44):32200-7.
3. ↑ ^{3.0 3.1} Blixt O, Head S, Mondala T, Scanlan C, Huflejt ME, Alvarez R, Bryan MC, Fazio F, Calarese D, Stevens J, Razi N, Stevens DJ, Skehel JJ, van Die I, Burton DR, Wilson IA, Cummings R, Bovin N, Wong CH, Paulson JC. Printed covalent glycan array for ligand profiling of diverse glycan binding proteins. Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17033-8.

Acknowledgements

The CFG is grateful to the following PIs for their contributions to this wiki page: Paul Crocker, James Paulson