Abstract
BackgroundAlpha-dystroglycan (α-DG) is a cell surface receptor providing a molecular link between the extracellular matrix (ECM) and the actin-based cytoskeleton. During its biosynthesis, α-DG undergoes specific and unusual O-glycosylation crucial for its function as a high-affinity cellular receptor for ECM proteins.Methodology/Principal FindingsWe report that expression of functionally glycosylated α-DG during thymic development is tightly regulated in developing T cells and largely confined to CD4−CD8− double negative (DN) thymocytes. Ablation of DG in T cells had no effect on proliferation, migration or effector function but did reduce the size of the thymus due to a significant loss in absolute numbers of thymocytes. While numbers of DN thymocytes appeared normal, a marked reduction in CD4+CD8+ double positive (DP) thymocytes occurred. In the periphery mature naïve T cells deficient in DG showed both normal proliferation in response to allogeneic cells and normal migration, effector and memory T cell function when tested in acute infection of mice with either lymphocytic choriomeningitis virus (LCMV) or influenza virus.Conclusions/SignificanceOur study demonstrates that DG function is modulated by glycosylation during T cell development in vivo and that DG is essential for normal development and differentiation of T cells.
Highlights
Alpha-dystroglycan (a-DG) is an important cell surface receptor with high affinity for the extracellular matrix (ECM) proteins laminin, agrin, perlecan, and neurexin [1] and serves as a cellular receptor for several arenavirises, including lymphocytic choriomeningitis virus (LCMV) and the pathogenic Lassa virus (Cao et al, 1998)
During T Cell Development To assess the biological role of a-DG in T cell development, we first examined the expression of functionally glycosylated aDG on different subsets of thymocytes based on their expression of CD4 and CD8
Using a monoclonal antibody IIH6 recognizing functionally glycosylated a-DG [18], high levels of glycosylated a-DG were detected in double negative (DN) thymocytes, whereas by contrast only low levels were found on double positive (DP) and both CD4+ and CD8+ single positive (SP) thymocytes (Fig. 1A, top)
Summary
Alpha-dystroglycan (a-DG) is an important cell surface receptor with high affinity for the extracellular matrix (ECM) proteins laminin, agrin, perlecan, and neurexin [1] and serves as a cellular receptor for several arenavirises, including lymphocytic choriomeningitis virus (LCMV) and the pathogenic Lassa virus (Cao et al, 1998). While the core protein of DG is ubiquitously expressed, functional glycosylation of a-DG is regulated both in the developing and adult organism. While the function of DG in muscle, brain, and other organs becomes increasingly clear, the role of this important ECM receptor in the immune system is largely unknown. Alpha-dystroglycan (a-DG) is a cell surface receptor providing a molecular link between the extracellular matrix (ECM) and the actin-based cytoskeleton. A-DG undergoes specific and unusual Oglycosylation crucial for its function as a high-affinity cellular receptor for ECM proteins
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