CD22-Binding Synthetic Sialosides Regulate B Lymphocyte Proliferation Through CD22 Ligand-Dependent and Independent Pathways, and Enhance Antibody Production in Mice

Frontiers in Immunology

Hiromune Ando¹  Hideharu Ishida¹  Jamey D. Marth²  Akihiro Imamura³  Natsuki Watanabe³  Hajjaj Abdu-Allah³  Akiharu Ueki³  Makoto Kiso³  Hiromu Takematsu⁴  Thomas F. Tedder⁵  Chizuru Akatsu⁶  Hongrui Yang⁶  Tatsuya Yonemizu⁶  Naoko Matsubara⁶  Takeshi Tsubata⁶  Nobutaka Numoto⁷  Nobutoshi Ito⁷  Shinobu Kitazume⁸ 

[1] Center for Highly Advanced Integration of Nano and Life Sciences (G-CHAIN), Gifu University, Gifu, Japan;Center for Nanomedicine, University of California, Santa Barbara, CA, United States;Department of Applied Bio-Organic Chemistry, Gifu University, Gifu, Japan;Department of Biological Chemistry, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan;Department of Immunology, Duke University Medical Center, Durham, NC, United States;Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan;Department of Structural Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan;RIKEN, Wako, Saitama, Japan;

关键词: CD22;    glycan ligands;    synthetic sialoside;    adjuvant;    B cell;   

DOI  :  10.3389/fimmu.2018.00820

来源: DOAJ

【 摘 要 】

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are expressed in various immune cells and most of them carry signaling functions. High-affinity synthetic sialoside ligands have been developed for various Siglecs. Therapeutic potentials of the nanoparticles and compounds that contain multiple numbers of these sialosides and other reagents such as toxins and antigens have been demonstrated. However, whether immune responses can be regulated by monomeric sialoside ligands has not yet been known. CD22 (also known as Siglec-2) is an inhibitory molecule preferentially expressed in B lymphocytes (B cells) and is constitutively bound and functionally regulated by α2,6 sialic acids expressed on the same cell (cis-ligands). Here, we developed synthetic sialosides GSC718 and GSC839 that bind to CD22 with high affinity (IC50 ~100 nM), and inhibit ligand binding of CD22. When B cells are activated by B cell antigen receptor (BCR) ligation, both GSC718 and GSC839 downregulate proliferation of B cells, and this regulation requires both CD22 and α2,6 sialic acids. This result suggests that these sialosides regulate BCR ligation-induced B cell activation by reversing endogenous ligand-mediated regulation of CD22. By contrast, GSC718 and GSC839 augment B cell proliferation induced by TLR ligands or CD40 ligation, and this augmentation requires CD22 but not α2,6 sialic acids. Thus, these sialosides appear to enhance B cell activation by directly suppressing the inhibitory function of CD22 independently of endogenous ligand-mediated regulation. Moreover, GSC839 augments B cell proliferation that depends on both BCR ligation and CD40 ligation as is the case for in vivo B cell responses to antigens, and enhanced antibody production to the extent comparable to CpG oligonuleotides or a small amount of alum. Although these known adjuvants induce production of the inflammatory cytokines or accumulation of inflammatory cells, CD22-binding sialosides do not. Thus, synthetic sialosides that bind to CD22 with high-affinity modulate B cell activation through endogenous ligand-dependent and independent pathways, and carry an adjuvant activity without inducing inflammation.

【 授权许可】

Unknown