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Cross-Linking of GM1 Ganglioside by Galectin-1 Mediates Regulatory T Cell Activity Involving TRPC5 Channel Activation: Possible Role in Suppressing Experimental Autoimmune Encephalomyelitis¹

Jianfeng Wang^*, Zi-Hua Lu^*, Hans-Joachim Gabius, Christine Rohowsky-Kochan^*, Robert W. Ledeen^2,* and Gusheng Wu^2,*

^* Department of Neurology & Neurosciences, New Jersey Medical School-University of Medicine and Dentistry of New Jersey, Newark, NJ 07103; and Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig Maximillians University, Munich, Germany

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 Ca²⁺ influx upon GM1 cross-linking by Gal-1 or CtxB. This involved co-cross-linking of heterodimeric integrin due to close association of these ₄β₁ and ₅β₁ 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 Ca²⁺ 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant NS033912 (to R.W.L.).

² Address correspondence and reprint requests to Dr. Robert Ledeen and Dr. Gusheng Wu, Department of Neurology & Neurosciences, New Jersey Medical School-UMDNJ, 185 South Orange Avenue, Newark, NJ 07103. E-mail addresses: ledeenro{at}umdnj.edu and gwu{at}umdnj.edu

³ Abbreviations used in this paper: Treg, regulatory T; CtxB, B subunit of cholera toxin; [Ca²⁺]i, intracellular Ca²⁺ concentration; EAE, experimental autoimmune encephalomyelitis; Gal-1, galectin-1; Gg, gangliotetraose ganglioside; HPTLC, high-performance TLC; IP, immunoprecipitation; KO, knockout; MOG, myelin oligodendrocyte glycoprotein; Teff, effector T; shRNA, short hairpin RNA; WT, wild type; TRPC5, transient receptor potential canonical form 5.