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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 ^,

Yuko Naito,^1,7 Hiromu Takematsu,^1,7 Susumu Koyama,² Shizu Miyake,² Harumi Yamamoto,⁵ Reiko Fujinawa,⁵ Manabu Sugai,⁴ Yasushi Okuno,³ Gozoh Tsujimoto,³ Toshiyuki Yamaji,⁵ Yasuhiro Hashimoto,^5,7 Shigeyoshi Itohara,⁶ Toshisuke Kawasaki,^2, Akemi Suzuki,⁵ and Yasunori Kozutsumi^1,5,7*

Laboratory of Membrane Biochemistry and Biophysics, Graduate School of Biostudies,¹ Department of Biological Chemistry,² Department of Genomic Drug Discovery, Graduate School of Pharmaceutical Sciences,³ Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Sakyo, Kyoto 606-8501, Japan,⁴ Supra-Biomolecular System Research Group, RIKEN Frontier Research System,⁵ Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, RIKEN, Wako, Saitama 351-0198, Japan,⁶ CREST, Japan Science and Technology, Kawaguchi, Saitama, Japan⁷

Received 2 November 2006/ Returned for modification 9 January 2007/ Accepted 30 January 2007

Sialic acid (Sia) is a family of acidic nine-carbon sugars that occupies the nonreducing terminus of glycan chains. Diversity of Sia is achieved by variation in the linkage to the underlying sugar and modification of the Sia molecule. Here we identified Sia-dependent epitope specificity for GL7, a rat monoclonal antibody, to probe germinal centers upon T cell-dependent immunity. GL7 recognizes sialylated glycan(s), the 2,6-linked N-acetylneuraminic acid (Neu5Ac) on a lactosamine glycan chain(s), in both Sia modification- and Sia linkage-dependent manners. In mouse germinal center B cells, the expression of the GL7 epitope was upregulated due to the in situ repression of CMP-Neu5Ac hydroxylase (Cmah), the enzyme responsible for Sia modification of Neu5Ac to Neu5Gc. Such Cmah repression caused activation-dependent dynamic reduction of CD22 ligand expression without losing 2,6-linked sialylation in germinal centers. The in vivo function of Cmah was analyzed using gene-disrupted mice. Phenotypic analyses showed that Neu5Gc glycan functions as a negative regulator for B-cell activation in assays of T-cell-independent immunization response and splenic B-cell proliferation. Thus, Neu5Gc is required for optimal negative regulation, and the reaction is specifically suppressed in activated B cells, i.e., germinal center B cells.

Published ahead of print on 12 February 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

Present address: Research Center for Glycobiotechnology, Ritsumeikan University, Kyoto, Japan.

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