Development of effective antibody (Ab) responses is critically dependent on the recruitment of nave B cells into secondary lymphoid organs and, upon antigen activation, their coordinated differentiation into germinal center (GC) B cells to memory B cells and Ab-producing plasma cells. Knowing which mechanistic factors control B cell subset transition with the therapeutic goal of Ab-boosting or -attenuating activity, however, is still poorly understood. Exciting new published data from our laboratory highlight striking differences in the glycomic signatures of human nave, GC and memory B cell subsets featured by either i-linear or I-branched poly-N-acetyllactosamines (poly-LacNAcs). Whereas GC B cells express mainly I-branched poly-LacNAcs, nave/memory B cells display principally i-linear poly-LacNAcs, which enable robust binding to immuno- modulator, galectin (Gal)-9. Gal-9-binding causes downstream inhibition of cell proliferation, activation and signaling related to BCR-engagement while, interestingly, evoking a pro-survival activity. Given the selective Gal-9-binding to naive/memory B cells, we speculate that Gal-9 serves as a physiologic ?tuner? of peripheral B cell activation and B cell reactivity. Other key data on the distribution of Gal-9 in ?reactive? lymph node (LN)- like tonsil tissue reveal that, while nave B cells express endogenous Gal-9, Gal-9 expression is strongest on high endothelial venules (HEV). Since HEVs initiate adhesive contact with circulating nave/memory B cells and are densely packed in the cortex adjacent to B cell follicles, HEVs are strategically poised to elicit Gal-9- dependent adhesion/regulation. The spatial, cellular and functional control of Gal-9 on B cells in lymphoid organs is still unknown and a major gap in the field of galectin immunology. Our guiding hypothesis is that Gal- 9 on HEV can bind circulating nave/memory B cells and help recruit them into LNs as well as transmit regulatory signals as B cells traverse the endothelium and enter B cell follicles. In this exploratory proposal, we will examine the function of human endothelial cell (EC)-derived Gal-9 on human nave B cell adhesion and immunoregulation and will assay for B cell homing to peripheral LNs in the presence/absence of Gal-9.
The Specific Aims are: 1.) To study Gal-9-dependent vascular EC ? B cell adhesive interactions and 2.) To analyze immunoregulatory effects of Gal-9 expressed by cytokine-activated human ECs on human nave B cells. We will employ our unique experience and innovative primary human cell models, adhesion assays, mutant mice, gene editing methods to study whether Gal-9 on ECs supports nave B cell adhesion, LN-homing as well as trigger immunoregulatory activity. These exploratory studies directly challenge current dogma that galectins largely function as immunoregulators, offering an alternative role for Gal-9 in facilitating B cell-EC adhesion, LN-homing and in situ peripheral control of B cell activity. Importantly, our findings will reveal novel targets for modulating B cell immunity and provide necessary data for a grant larger in scope.

Public Health Relevance

The efficiency of antibody-immune responses against infections is dependent on the strategic localization and functional prowess of antibody-producing B cells in peripheral immune tissues. We have recently uncovered unique cell surface carbohydrate features on B cells that allow binding to potent immunomodulator proteins found at a high level in these tissues and regulate B cell reactivity. The overall objective of the grant is to understand whether and how these B cell carbohydrate ? immunomodulator protein interactions potentially help B cell recruitment and function in peripheral immune tissues. Importantly, our results will provide a firm foundation of future research larger in scope that will ultimately lead to new therapies designed to either curb or enhance antibody responses.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Intercellular Interactions Study Section (ICI)
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Ferguson, Stacy E
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Florida International University
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