Unmasking of CD22 Co-receptor on Germinal Center B-cells Occurs by Alternative Mechanisms in Mouse and Man

Macauley, Matthew S.; Kawasaki, Norihito; Peng, Wenjie; Wang, Shuihua; He, Yuan; Arlian, Britni M.; McBride, Ryan; Kannagi, Reiji; Khoo, Kay‐Hooi; Paulson, James C.

doi:10.1074/jbc.m115.691337

Cited by 54 publications

(83 citation statements)

References 36 publications

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“…Cognate interactions between B and T cells are critical for GC initiation and maintenance, and CD22 ligands are expressed on T cells as well as B cells [11,27]. Interestingly, high affinity ligands for CD22, while present on naïve and memory B cells, are lost on GC B cells [28]. Thus, one attractive possibility is that once CD22 is unmasked on GC B cells, CD22L-CD22 interactions may then occur in trans between CD22L + CD4 T FH cells and CD22 + GC B cells to promote further B cell survival and maturation.…”

Section: Resultsmentioning

confidence: 99%

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CD22 is required for formation of memory B cell precursors within germinal centers

2017

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CD22 is a BCR co-receptor that regulates B cell signaling, proliferation and survival and is required for T cell-independent Ab responses. To investigate the role of CD22 during T cell-dependent (TD) Ab responses and memory B cell formation, we analyzed Ag-specific B cell responses generated by wild-type (WT) or CD22-/- B cells following immunization with a TD Ag. CD22-/- B cells mounted normal early Ab responses yet failed to generate either memory B cells or long-lived plasma cells, whereas WT B cells formed both populations. Surprisingly, B cell expansion and germinal center (GC) differentiation were comparable between WT and CD22-/- B cells. CD22-/- B cells, however, were significantly less capable of generating a population of CXCR4hiCD38hi GC B cells, which we propose represent memory B cell precursors within GCs. These results demonstrate a novel role for CD22 during TD humoral responses evident during primary GC formation and underscore that CD22 functions not only during B cell maturation but also during responses to both TD and T cell-independent antigens.

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Section: Resultsmentioning

confidence: 99%

“…Biotinylated I-Ealpha peptide was synthesized by Invitrogen and used to generate both NP-streptavidin-I-Ealpha and NP-streptavidin-AF647-I-Ealpha which were prepared and tested in control experiments as described [28]. …”

Section: Methodsmentioning

confidence: 99%

CD22 is required for formation of memory B cell precursors within germinal centers

2017

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“…In this aspect, it is satisfying that hCD22 on our transgenic B-cells high degree of colocalization with mCD22, demonstrating the cis glycan ligands on murine B-cells are sufficient to regulate hCD22 localization. Although the predominant type of sialic acid on murine B-cells is α2-6-linked N -glycolylneuraminic acid (Neu5Gc), while on human B-cells it is α2-6-linked N -acetylneuraminic acid (Neu5Ac), it is noteworthy that hCD22 does not discriminate between these two types of sialic acid, unlike mCD22 that strongly prefers the glycolyl version(29, 70). The ability of hCD22 to recognize sialic acid glycan-containing glycan ligands on mouse B-cells is likely a key factor in its ability to functionally substitute for mCD22 in the various aspects we report herein.…”

Section: Discussionmentioning

confidence: 99%

“…While these are roles for trans ligands, cis ligands also have the potential playing a role in these events since cis ligands ‘mask’ the ability of CD22 to interact with trans ligands. Altered masking of CD22, such as the ‘unmasking’ of CD22 in the germinal center (GC) that occurs through subtle changes in glycan ligands on GC B-cells, has the potential to fine tune the activity of B-cells in different ways(29). In this regard, it is noteworthy that defects in memory B-cell formation were recently been reported in CD22 −/− mice(30).…”

Section: Introductionmentioning

confidence: 99%

Human CD22 Inhibits Murine B Cell Receptor Activation in a Human CD22 Transgenic Mouse Model

Bednar

Shanina

Ballet

et al. 2017

The Journal of Immunology

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CD22, a sialic-acid binding immunoglobulin type-lectin (Siglec) family member, is an inhibitory co-receptor of the B-cell receptor (BCR) with established roles in health and disease. The restricted expression pattern of CD22 on B-cells and most B-cell lymphomas has made CD22 a therapeutic target for B-cell-mediated diseases. Models to better understand how in vivo targeting of CD22 translates to human disease are needed. Here, we report development of a transgenic mouse expressing human CD22 (hCD22) in B-cells and assess its ability to functionally substitute for murine CD22 (mCD22) for regulation of BCR signaling, antibody responses, homing, and tolerance. Expression of hCD22 on transgenic murine B-cells is comparable to expression on human primary B-cells, and co-localizes with mCD22 on the cell surface. Murine B-cells expressing only hCD22 have identical calcium (Ca2+) flux responses in response to anti-IgM as mCD22-expressing WT B-cells. Furthermore, hCD22 transgenic mice on a mCD22−/− background have restored levels of marginal zone B-cells and antibody responses compared to deficiencies observed in CD22−/− mice. Consistent with these observations, hCD22 transgenic mice develop normal humoral responses in a peanut allergy oral sensitization model. Homing of B-cells to Peyer’s patches (PP) was partially rescued by expression of hCD22 compared to CD22−/− B-cells, although not to WT levels. Notably, Siglec-engaging antigenic liposomes (STALs) formulated with a hCD22 ligand were shown to prevent B-cell activation, increase cell death, and induce tolerance in vivo. This hCD22 transgenic mouse will be a valuable model for investigating the function of hCD22 and pre-clinical studies targeting hCD22.

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“…However, there are important caveats. Firstly, the microbiology of the mouse varies to that in the human gut [ 338 ], secondly, the glycobiology of the mouse gastric mucosa also varies to that in man [ 339 ], and finally there are immunological differences [ 340 ]. Together these caveats make comparison with the human gut difficult and unpredictable.…”

Section: Glycan Expression When the Gastrointestinal Microbiota Ismentioning

confidence: 99%

The Interaction of the Gut Microbiota with the Mucus Barrier in Health and Disease in Human

Corfield

2018

Microorganisms

101

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Glycoproteins are major players in the mucus protective barrier in the gastrointestinal and other mucosal surfaces. In particular the mucus glycoproteins, or mucins, are responsible for the protective gel barrier. They are characterized by their high carbohydrate content, present in their variable number, tandem repeat domains. Throughout evolution the mucins have been maintained as integral components of the mucosal barrier, emphasizing their essential biological status. The glycosylation of the mucins is achieved through a series of biosynthetic pathways processes, which generate the wide range of glycans found in these molecules. Thus mucins are decorated with molecules having information in the form of a glycocode. The enteric microbiota interacts with the mucosal mucus barrier in a variety of ways in order to fulfill its many normal processes. How bacteria read the glycocode and link to normal and pathological processes is outlined in the review.

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Unmasking of CD22 Co-receptor on Germinal Center B-cells Occurs by Alternative Mechanisms in Mouse and Man

Cited by 54 publications

References 36 publications

CD22 is required for formation of memory B cell precursors within germinal centers

CD22 is required for formation of memory B cell precursors within germinal centers

Human CD22 Inhibits Murine B Cell Receptor Activation in a Human CD22 Transgenic Mouse Model

The Interaction of the Gut Microbiota with the Mucus Barrier in Health and Disease in Human

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