title: The N- and C-terminal carbohydrate recognition domains of galectin-9 contribute differently to its multiple functions in innate immunity and adaptive immunity.
abstract: By binding to T cell Ig mucin-3 (Tim-3) expressed on different cells, galectin-9 (Gal-9) mediates two important functions, triggering T cell death and activating innate immune cells. The mechanisms by which ligation of the same molecule on different cell types mediates different effects are largely unclear. Gal-9 contains two carbohydrate recognition domains (CRD) in the N- and C-terminal regions (Gal-9-N and Gal-9-C). The N and C terminals of Gal-9 have been shown to have different activities in promoting T cell death. However, whether the differences between two domains account for its dual functions remains to be elucidated. Here we hypothesized that the different functions of Gal-9 in innate immunity and adaptive immunity are mediated by different domains. To test this, we created recombinant Gal-9 (Gal-9-NC) and homodimers containing either the NCRD (Gal-9-N) or the CCRD (Gal-9-C). All these Gal-9 constructs can activate dendritic cells (DCs) and induce T cell death. However, the Gal-9-C was much more potent than the Gal-9-N in inducing T cell death, while the Gal-9-N was much more effective in activating DCs by inducing much higher TNF-α and IL-6 production, greater phosphorylation of p38 and AKT. In both DC and T cells, Gal-9-N but not Gal-9-C stimulation resulted in markedly iκBα degradation. Finally, computer analyses suggested different patterns and affinities for the binding of the Gal-9-N and Gal-9-C to their receptor, Tim-3. Our data suggest that the N- and C-terminal CRDs of Gal-9 contribute differently to its ability to induce T cell death and to activate DCs. Further investigations on the underlying mechanisms will provide new insights into the biochemical basis for the multiple activities of Gal-9.
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Li
authors.forename: Jiannan
authors.initials: J
authors.lastname: Feng
authors.forename: Shaoxia
authors.initials: S
authors.lastname: Geng
authors.forename: Shusheng
authors.initials: S
authors.lastname: Geng
authors.forename: Huawei
authors.initials: H
authors.lastname: Wei
authors.forename: Guojiang
authors.initials: G
authors.lastname: Chen
authors.forename: Xinying
authors.initials: X
authors.lastname: Li
authors.forename: Liyan
authors.initials: L
authors.lastname: Wang
authors.forename: Renxi
authors.initials: R
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Gencheng
authors.initials: G
authors.lastname: Han
authors.forename: Beifen
authors.initials: B
authors.lastname: Shen
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002241:Carbohydrates / Q000737:chemistry*; D016923:Cell Death; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D037161:Galectins / Q000737:chemistry* / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification; D013329:Structure-Activity Relationship
chemical_list: D002241:Carbohydrates; D037161:Galectins; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D011991:Receptors, Virus; D011994:Recombinant Proteins; C508186:galectin 9, mouse