International Immunology Advance Access originally published online on February 29, 2008
International Immunology 2008 20(4):591-600; doi:10.1093/intimm/dxn018
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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
Vaccine Department, Centre of Molecular Immunology, 216 esq 15, Atabey, Playa, PO Box 16040, Havana, Cuba
Correspondence to: J. León; E-mail: yoel{at}cim.sld.cu
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.
Keywords: CD4+ T cells, dendritic cells, immune dysfunction, NGcGM3
Transmitting editor: G. J. Hämmerling
Received 1 October 2007, accepted 24 January 2008.