CD22

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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.

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Contents

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. Differences in the specificity of human and murine siglec orthologs/paralogs also reflect adaptations to recognize self-ligands [1][4]. In particular, murine CD22 preferentially recognizes NeuGc containing α2-6 sialosides (2) with over 10 fold higher affinity than NeuAc (1), but human CD22 exhibits equal affinity for both, consistent with the fact that mouse B cells preferentially express NeuGc, while human B cells express only NeuAc [5][6][7][8]. Another difference is that human CD22 exhibits highest affinity for the 6-sulfo-NeuAcα2-6Galβ1-4GlcNAc (3) [3][2][9]. Despite these differences, activation of B cells in both species results in down regulation of the highest affinity ligand. In murine B cells, activation causes de novo synthesis of sialosides with NeuAc instead of NeuGc through down regulation of CMP-sialic acid hydroxylase [7], while in human B cells, differentiation of B cells in germinal centers coincides with loss of the sulfate from the high affinity sulfated ligand (3) [2]. Recent reports also document that 9-O-acetyl substitutions of sialic acids also play an important role in regulating the association of CD22 with cis ligands, which is an element of specificity conserved across the two species [10][11][12][13].

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

CD22 is a co-receptor of the membrane IgM B cell receptor (BCR), and regulates BCR signaling via immunoreceptor tyrosine inhibitory motifs (ITIMs) in its cytoplasmic domain.[14][1][15][16] CD22 is predominately localized in clathrin-coated pits on the surface of the cell, where it mediates constitutive recycling to endocytic compartments.[17][18][19] Following ligation of the BCR with antigen, phosphokinases phosphorylate the BCR complex, which in turn amplifies a signal to activate the cell to proliferate and produce antibody. As one of the co-receptors of the BCR, CD22 recruits cofactors that modulate the degree of BCR phosphorylation and downstream signaling. In particular, CD22 recruits the phsophatase SHP-1 that dephosphorylates the BCR complex and suppresses cell signaling. Thus, CD22 is often considered to be a negative regulator of BCR signaling.

The roles of ligands in BCR signaling have been extensively investigated. [14][1][15][17][7][11][20] Siglecs in general, and CD22 in particular, are known to interact with sialylated ligands on the same cell, “in cis”, and on opposing cells, “in trans”. Although many B cell glycoproteins carry the ligand of CD22, the predominant cis ligands appear to be CD22 itself. [21] This is due in part to the fact that CD22 is preferentially concentrated in clathrin coated pits. Although there is agreement that cis ligand influence CD22 function as a regulator of BCR signaling, there is yet no consensus on the relevance of cis ligands to the constitutive regulation of the BCR. [14][15][17][7][11]

Despite the presence of cis ligands, CD22 can interact with trans ligands on opposing cells, and redistribute to the site of cell contact.[22] This property is has been implicated in recirculation of B cells in the bone marrow,[23] and is believed to be relevant to innate recognition of self. [24] [25] Indeed, Lanoue et al. demonstrated that B cell signaling is suppressed if the antigen is expressed on a cell that contains ligands of CD22. [24] Several groups have demonstrated that co-presentation of an antigen and CD22 ligands results in suppressed activation of a B cell.(14-16) [24][25][26] In fact, immunization of a mouse with a polymer containing both a T-independent antigen and a high affinity CD22 ligand induces activation and apoptosis of B cells recognizing the antigen, resulting in tolerization of the mouse to subsequent challenge with the antigen.[25] The results suggest that trans ligands of CD22 and other B cell siglecs may serve as markers of self, and that CD22 participates in a mechanism of peripheral tolerance to self-antigens.

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 1.4 1.5 1.6 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 2.3 2.4 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 3.2 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.
  4. Varki, A. Colloquium paper: uniquely human evolution of sialic acid genetics and biology. "Proc Natl Acad Sci U S A. 2010 May 11;107 Suppl 2:8939-46.
  5. Brinkman-Van der Linden EC, Sjoberg ER, Juneja LR, Crocker PR, Varki N, Varki A. Loss of N-glycolylneuraminic acid in human evolution. Implications for sialic acid recognition by siglecs. .J Biol Chem. 2000 Mar 24;275(12):8633-40.
  6. Kelm S, Schauer R, Manuguerra JC, Gross HJ, Crocker PR. Modifications of cell surface sialic acids modulate cell adhesion mediated by sialoadhesin and CD22. Glycoconj J. 1994 Dec;11(6):576-85.
  7. 7.0 7.1 7.2 7.3 Naito Y, Takematsu H, Koyama S, Miyake S, Yamamoto H, Fujinawa R, Sugai M, Okuno Y, Tsujimoto G, Yamaji T, Hashimoto Y, Itohara S, Kawasaki T, Suzuki A, Kozutsumi Y. Germinal center marker GL7 probes activation-dependent repression of N-glycolylneuraminic acid, a sialic acid species involved in the negative modulation of B-cell activation. Mol Cell Biol. 2007 Apr;27(8):3008-22.
  8. Blixt O, Collins BE, van den Nieuwenhof IM, Crocker PR, Paulson JC. Sialoside specificity of the siglec family assessed using novel multivalent probes: identification of potent inhibitors of myelin-associated glycoprotein. J Biol Chem. 2003 Aug 15;278(33):31007-19.
  9. Consortium for Functional Glycomics. http://www.functionalglycomics.org.
  10. Sjoberg ER, Powell LD, Klein A, Varki A. Natural ligands of the B cell adhesion molecule CD22 beta can be masked by 9-O-acetylation of sialic acids. J Cell Biol. 1994 Jul;126(2):549-62.
  11. 11.0 11.1 11.2 Cariappa A, Takematsu H, Liu H, Diaz S, Haider K, Boboila C, Kalloo G, Connole M, Shi HN, Varki N, Varki A, Pillai S. B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase. J Exp Med. 2009 Jan 16;206(1):125-38.
  12. Pillai S, Cariappa A, Pirnie SP. Esterases and autoimmunity: the sialic acid acetylesterase pathway and the regulation of peripheral B cell tolerance. Trends Immunol. 2009 Oct;30(10):488-93.
  13. Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J, Liu H, Bell DW, Driscoll DR, Diederichs S, Haider K, Netravali I, Le S, Elia R, Dow E, Lee A, Freudenberg J, De Jager PL, Chretien Y, Varki A, Macdonald ME, Gillis T, Behrens TW, Bloch D, Collier D, Korzenik J, Podolsky DK, Hafler D, Murali M, Sands B, Stone JH, Gregersen PK, Pillai S. Functionally defective germline variants of sialic acid acetylesterase in autoimmunity. Nature. 2010 Jul 8;466(7303):243-7.
  14. 14.0 14.1 14.2 Tedder TF, Poe JC, Haas KM. CD22: a multifunctional receptor that regulates B lymphocyte survival and signal transduction. Adv Immunol. 2005;88:1-50.
  15. 15.0 15.1 15.2 Walker JA, Smith KG. CD22: an inhibitory enigma. Immunology. 2008;123(3):314-25.
  16. Nitschke L. CD22 and Siglec-G: B-cell inhibitory receptors with distinct functions. Immunol Rev. 2009;230(1):128-43.
  17. 17.0 17.1 17.2 Collins BE, Smith BA, Bengtson P, Paulson JC. . Ablation of CD22 in ligand-deficient mice restores B cell receptor signaling. Nat Immunol. 2006;7(2):199-206.
  18. Grewal PK, Boton M, Ramirez K, Collins BE, Saito A, Green RS, Ohtsubo K, Chui D, Marth JD. ST6Gal-I restrains CD22-dependent antigen receptor endocytosis and Shp-1 recruitment in normal and pathogenic immune signaling. Mol Cell Biol. 2006;26(13):4970-81.
  19. O'Reilly MK, Tian H, Paulson JC. CD22 is a recycling receptor that can shuttle cargo between the cell surface and endosomal compartments of B cells. J Immunol. 2011;186(3):1554-63.
  20. Hennet T, Chui D, Paulson JC, Marth JD. Immune regulation by the ST6Gal sialyltransferase. Proc Natl Acad Sci U S A. 1998;95(8):4504-9.
  21. Han S, Collins BE, Bengtson P, Paulson JC. Homomultimeric complexes of CD22 in B cells revealed by protein-glycan cross-linking. Nat Chem Biol. 2005;1(2):93-7.
  22. Collins BE, Blixt O, DeSieno AR, Bovin N, Marth JD, Paulson JC. Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact. Proc Natl Acad Sci U S A. 2004;101(16):6104-9.
  23. Nitschke L, Floyd H, Ferguson DJ, Crocker PR. Identification of CD22 ligands on bone marrow sinusoidal endothelium implicated in CD22-dependent homing of recirculating B cells. J Exp Med. 1999;189(9):1513-8.
  24. 24.0 24.1 24.2 Lanoue A, Batista FD, Stewart M, Neuberger MS. Interaction of CD22 with alpha2,6-linked sialoglycoconjugates: innate recognition of self to dampen B cell autoreactivity?. Eur J Immunol. 2002;32(2):348-55.
  25. 25.0 25.1 25.2 Duong BH, Tian H, Ota T, Completo G, Han S, Vela JL, Ota M, Kubitz M, Bovin N, Paulson JC, Nemazee D. Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo. J Exp Med. 2010;207(1):173-87.
  26. Courtney AH, Puffer EB, Pontrello JK, Yang ZQ, Kiessling LL. Sialylated multivalent antigens engage CD22 in trans and inhibit B cell activation. 'Proc Natl Acad Sci U S A. 2009;106(8):2500-5.

Acknowledgements

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

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