期刊
BIOCHEMICAL JOURNAL
卷 434, 期 -, 页码 153-160出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20101691
关键词
galectin alternative inhibitor; glycan binding; lattice formation; T-cell activation
资金
- Agencia Nacional para la Promocion Cientifica y Tecnologica (ANPCyT), Argentina [PICT 2006-0168, PICT 2008-0369]
Gal (galectin)-8 is a tandem-repeat Gal containing N-CRDs (N-terminal carbohydrate-recognition domains) and C-CRDs (C-terminal carbohydrate-recognition domains) with differential glycan-binding specificity fused by a linker peptide. Gal-8 has two distinct effects On CD4 T-cells: at high concentrations it induces antigen-independent proliferation, whereas at low concentrations it co-stimulates antigen-specific responses. Associated Gal-8 structural requirements were dissected in the present study. Recombinant homodimers N-N (two N-terminal CRD chimaera) and C-C (two C-terminal CRD chimaera), but not single C-CRDs or N-CRDs, induced proliferation; however, single domains induced co-stimulation. These results indicate that the tandem-repeat structure: was essential only for the proliferative effect, suggesting the involvement of lattice formation, whereas co-stimulation could be mediated by agonistic interactions. In both cases, C-C chimaeras displayed higher activity than Gal-8, indicating that the C-CRD was mainly involved, as was further supported by the strong inhibition of proliferation and co-stimulation in the presence of blood group B antigen, specifically recognized by this domain. Classic Gal inhibitors (lactose and thiodigalactoside) prevented proliferation but not co-stimulatory activity, which was inhibited by 3-O-beta-D-galactopyranosyl-D-arabinose. Interestingly, Gal-8 induced proliferation of naive human CD4 Teens, varying from non- to high-responder individuals, whereas it promoted cell death of phytohaemagglutinin or CD3/CD28 pre-activated cells. The findings of the present study delineate the differential molecular requirements for Gal-8 activities on T-cells, and suggest a dual activity relying on activation state.
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