Differential influence of the tumour-specific non-human sialic acid containing GM3 ganglioside on CD4+CD25- effector and naturally occurring CD4+CD25+ regulatory T cells function.
Increasing evidences suggest that the aberrant expression of certain gangliosides on malignant cells could affect host's anti-tumour-specific immune responses. We have recently documented the relevance of the N-glycolylated variant of GM3 ganglioside (NGcGM3), a tumour-specific non-human sialic acid containing ganglioside, for tumour progression. However, evidences about the implication of host's immunity in NGcGM3-promoted cancer progression had not been obtained previously. In this work, we compared tumour growth of X63 myeloma cells pre-treated or not with an inhibitor of the glucosylceramide synthase enzyme, in wild or CD4+ T cell-depleted BALB/c mice. Results clearly showed a relationship between the agonistic effect of NGcGM3 in tumour growth and the presence of CD4+ T lymphocytes. For the first time, a description of a ganglioside-differential effect over purified CD4+CD25- and naturally occurring regulatory CD4+CD25+ T cells is provided. While NGcGM3 similarly down-modulated the CD4 expression in both cell populations, the inhibitory capacity of the CD4+CD25+ lymphocytes and their proliferation, induced by an anti-CD3 mAb and IL2, were not modified. In a different fashion, a reduction in proliferative capacity and a noteworthy secretion of anti-inflammatory cytokines were detected when CD4+CD25- T cells were cultured in the presence of NGcGM3. Considering the relevance of dendritic cells (DC) on primary activation of T cells, the effect of NGcGM3 over DC differentiation and TLR4-mediated maturation was also assessed. Our results indicate that NGcGM3 contributes to cancer progression mainly by influencing DC and CD4+CD25- T lymphocyte functions, rather than increasing the inhibitory capacity of naturally occurring regulatory T cells.
de León
Joel
J
Vaccine Department, Centre of Molecular Immunology, 216 esq 15, Atabey, Playa, PO Box 16040, Havana, Cuba. yoel@cim.sld.cu
Fernández
Audry
A
Clavell
Marilyn
M
Labrada
Mayrel
M
Bebelagua
Yanin
Y
Mesa
Circe
C
Fernández
Luis E
LE
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005679:G(M3) Ganglioside / Q000031:analogs & derivatives* / Q000276:immunology; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors; D007376:Interleukin-2 / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D019158:N-Acetylneuraminic Acid / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015295:Antigens, Tumor-Associated, Carbohydrate; D016207:Cytokines; D004791:Enzyme Inhibitors; D005679:G(M3) Ganglioside; D007376:Interleukin-2; C044298:N-glycolylneuraminyllactosylceramide; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D019158:N-Acetylneuraminic Acid