title: Cross-linking of GM1 ganglioside by galectin-1 mediates regulatory T cell activity involving TRPC5 channel activation: possible role in suppressing experimental autoimmune encephalomyelitis.
abstract: Several animal autoimmune disorders are suppressed by treatment with the GM1 cross-linking units of certain toxins such as B subunit of cholera toxin (CtxB). Due to the recent observation of GM1 being a binding partner for the endogenous lectin galectin-1 (Gal-1), which is known to ameliorate symptoms in certain animal models of autoimmune disorders, we tested the hypothesis that an operative Gal-1/GM1 interplay induces immunosuppression in a manner evidenced by both in vivo and in vitro systems. Our study of murine experimental autoimmune encephalomyelitis (EAE) indicated suppressive effects by both CtxB and Gal-1 and further highlighted the role of GM1 in demonstrating enhanced susceptibility to EAE in mice lacking this ganglioside. At the in vitro level, polyclonal activation of murine regulatory T (Treg) cells caused up-regulation of Gal-1 that was both cell bound and released to the medium. Similar activation of murine CD4(+) and CD8(+) effector T (Teff) cells resulted in significant elevation of GM1 and GD1a, the neuraminidase-reactive precursor to GM1. Activation of Teff cells also up-regulated TRPC5 channels which mediated Ca(2+) influx upon GM1 cross-linking by Gal-1 or CtxB. This involved co-cross-linking of heterodimeric integrin due to close association of these alpha(4)beta(1) and alpha(5)beta(1) glycoproteins with GM1. Short hairpin RNA (shRNA) knockdown of TRPC5 in Teff cells blocked contact-dependent proliferation inhibition by Treg cells as well as Gal-1/CtxB-triggered Ca(2+) influx. Our results thus indicate GM1 in Teff cells to be the primary target of Gal-1 expressed by Treg cells, the resulting co-cross-linking and TRPC5 channel activation contributing importantly to the mechanism of autoimmune suppression.
authors.affiliation: Department of Neurology & Neurosciences, University of Medicine and Dentistry of New Jersey, Newark, 07103, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wang
authors.forename: Zi-Hua
authors.initials: ZH
authors.lastname: Lu
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Gabius
authors.forename: Christine
authors.initials: C
authors.lastname: Rohowsky-Kochan
authors.forename: Robert W
authors.initials: RW
authors.lastname: Ledeen
authors.forename: Gusheng
authors.initials: G
authors.lastname: Wu
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002772:Cholera Toxin / Q000276:immunology / Q000378:metabolism; D003432:Cross-Linking Reagents; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D005677:G(M1) Ganglioside / Q000276:immunology / Q000378:metabolism*; D037483:Galectin 1 / Q000276:immunology / Q000378:metabolism*; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D050052:TRPC Cation Channels / Q000276:immunology*
chemical_list: D003432:Cross-Linking Reagents; D037483:Galectin 1; D050052:TRPC Cation Channels; C112021:Trpc5 protein, mouse; D005677:G(M1) Ganglioside; D002772:Cholera Toxin