Chemical residues of ganglioside molecules involved in interactions with lymphocyte surface targets leading to CD4 masking and inhibition of mitogenic proliferation

Abstract

Human lymphocyte CD4 becomes undetectable in the presence of exogenous gangliosides (CD4 masking), as originally described by Offner et al. (J. Immunol. 1987. 139: 3295). CD4 masking is apparently due to in situ rearrangement of the glycoprotein; since no direct binding of ganglioside to CD4 could be demonstrated, it was suggested that the effect could be mediated by interactions with other, as yet unidentified, surface structures. To gain insight into the structural requirements of the interaction(s) that leads to CD4 masking, we assayed the effects of a battery of gangliosides and of ganglioside derivatives on (a) CD4 masking; (b) cholera toxin binding (as a well known ganglioside-protein interaction) and (c) inhibition of lymphocyte mitogenic proliferation (as a second ganglioside interaction with a lymphocyte surface target). Our results indicate that the three interactions are distinctly different, since ganglioside chemical groups which are essential for one of the interactions are irrelevant for the others, and lead to the conclusion that gangliosides can interact with lymphocyte surface targets in a number of ways, causing a number of independent biological effects.

T Cell Numbers Relate to Bone Involvement in Gaucher Disease

“…The finding of a statistically significant correlation between the number of CD8 ϩ T lymphocytes and increased TRAP activity (a putative marker of osteoclastic activity) is indeed in keeping with the observations reported in vitro. The finding of low CD4 ϩ T lymphocytes is also of particular interest in view of earlier work where an increase in GM3 ganglioside was reported in tissues of Gaucher disease patients (29) and more recent studies showing that gangliosides interaction with CD4 favors its internalization and degradation (30,31).…”

Monosialoganglioside GM3 Induces CD4 Internalization in Human Peripheral Blood T Lymphocytes

“…The rapid insertion of gangliosides into the lipid bilayer of CD4* lymphocytes has been observed by Repke et al [11], who reported that the fusion process requires 1-3 min although the complete disappearance of CD4 from the cell surface requires 60 min. Since no direct binding of ganglioside to CD4 has been demonstrated [9], it is possible that the effect could be mediated by interactions with other, as yet unidentified, structures. Indeed, the oligosaccharide chains of gangliosides, protruding from the membrane surface, are available for a variety of interactions with other membrane components and with different external ligands.…”

“…The ganglioside effect was shown to be both temperature and dose-dependent, reversible within 24 h after ganglioside removal and completely neutralized by addition of 10% human serum 16]. Some reports suggest that this phenomenon may be due to the masking of CD4 epitopes [6,9,13] or to the shedding of CD4 containing proteins [16]. Other reports provided evidence for ganglioside-induced CD4 endocytosis [6,7,II,12].…”

Glycosphingolipids of Rat T Cells. Predominance of Asialo-GM1 and GD1c

“…The potent immunosuppressive activity of specific gangliosides together with the observation that high concentrations of gangliosides are present in patients with certain types of tumors led to the suggestion that cellular immunodeficiency and associated diminished T cell responses frequently associated with cancer are due to shedding of gangliosides by tumors [reviewed in Ladisch et al (1992)]. Furthermore, ganglioside GM1 also modulated CD4 surface expression on T cells (Offner et al, 1987;Grassi et al, 1990;Morrison et al, 1993). Recently, it was also shown that GM1-induced CD4 down regulation (Repke et al, 1992) was accompanied by CD4 degradation, which was To gain further insight into the functions of gangliosides in lymphocyte activation, ganglioside-binding proteins, such as toxins (Spiegel et al, 1985;Spiegel, 1989;Olivera & Spiegel, 1992) or antiganglioside antibodies (Hakomori, 1990;Hersey et al, 1989), which interact specifically with individual gangliosides on the cell surface, were used.…”