Role of CD22 in the Germinal Center Reaction

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Cell surface glycosylation is dynamic and often changes in response to cellular differentiation. Changes in glycosylation can impart a function to cells through glycan-binding proteins. Well-documented changes in cellular glycosylation occur in an immune response when B-cells differentiate into germinal center (GC) B cells. Immunologists routinely use these changes in glycosylation to identify the GC, using the antibody GL7, which is a structure within secondary lymphoid organs where antibody affinity maturation takes place. Remarkably, no function has been attributed to these changes in glycosylation. The change in glycosylation detected by GL7 is intriguing because of its relevance to CD22, a glycan-binding protein and member of the Siglec family of immunomodulatory receptors. CD22 is a negative regulator of the B-cell receptor (BCR) through its ability to recruit the phosphatase SHP-1, although its function in GC B-cells has remained largely unexplored. Specifically, GL7 recognizes a glycan that is a low affinity ligand for CD22; hence, GC B-cells loose the high affinity glycan ligand of CD22 found abundantly on naïve B-cells. High affinity glycan ligands of CD22 regulate its spatial organization on the surface of naïve B-cells, maintaining CD22 and BCR in different microdomains. Accordingly, we hypothesize that loss of high affinity CD22 ligands in GC B-cells promotes the association of CD22 with the BCR. This hypothesis is particularly intriguing in light of recent findings demonstrating that BCR signaling is inhibited in GC B-cells through constitutive co-localization of SHP-1 with the BCR. This project aims to test this hypothesis by assessing: (Aim1) the functional consequence of modulating expression of CD22 or its glycan ligands specifically in GC B-cells; (Aim2) whether changes in glycan ligands in GC B-cells drives co-localization of CD22 with the BCR, which is responsible for recruitment SHP-1 and inhibiting BCR signaling; and (3) the consequence of disrupting the function of CD22 in the context of an antibody-mediated autoimmune disease. Key to testing the hypothesis is a transgenic mouse we have established that maintains expression of high affinity glycan ligands for CD22 in GC B-cells. Preliminary results demonstrate that maintaining high affinity CD22 ligands in GC B-cells results in decreased competitiveness for the GC B-cell repertoire in competition with WT GC B-cells; an effect that requires expression of CD22. If preliminary results reflect a truly GC-specific role for CD22, we expect that modulating expression of CD22 or its glycan ligands in a GC-specific manner will likewise impair GC B-cell responses, increase BCR signaling in GC B-cells, and abrogate disease progression in a mouse model of antibody- mediated autoimmune disease. The long-term objective of this project is to establish the role(s) played by CD22 in the GC reaction in both health and disease. This knowledge will provide new insights into how an ongoing immune response can be modulated to treat an antibody-mediated autoimmune disease.