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 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 α4β1 and α5β1 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.

How adhesion/growth‐regulatory galectins‐1 and ‐3 attain cell specificity: Case study defining their target on neuroblastoma cells (SK‐N‐MC) and marked affinity regulation by affecting microdomain organization of the membrane

“…Previous work showing galectin-1 to be a major receptor for ganglioside GM1 (6) points to this as the likely functional ganglioside. A compensation of the inhibitor-dependent ganglioside deficit by glycoprotein glycans is not operative, as has also been seen in vivo for galectin-1 binding to T cells of mice lacking GM2/GD2 synthase (19). In the latter study, Ca 21 influx occurred after crosslinking as also seen for two other ganglioside GM1-specific probes, i.e.…”

Biochemical and Electrophysiological Modification of Amyloid Transthyretin on Cardiomyocytes

“…This hypothesis is in line with previous findings (31,55,64) and with the data presented here, which show a preferential interaction of TTR aggregates with GM1-rich sites, presumably in lipid rafts. Of note, GM1-rich sites have been shown to colocalize with and modulate ion channel function in the plasma membrane of different cell types (65)(66)(67)(68)(69)(70), and with the sodium calcium exchanger in the nuclear envelope of CMs (71).…”

Galectin-1 sensitizes carcinoma cells to anoikis via the fibronectin receptor α5β1-integrin

“…Enhanced caspase-8 activation by death receptors, such as CD95, following recruitment to lipid rafts and endocytosis provides an example for modulation of apoptotic signaling by endocytotic trafficking. 35 Association of ganglioside GM1, which by itself is a potent Gal-1 counterreceptor, with this integrin, as noted in T effector cells, 36 may favor clustering in cholesterol-enriched microdomains, leading to enhanced Gal-1 reactivity 37 thereby supporting recruitment to microdomains and endocytosis.…”