INCREASED PROLIFERATION, CYTOTOXICITY, AND GENE-EXPRESSION AFTER STIMULATION OF HUMAN PERIPHERAL-BLOOD T-LYMPHOCYTES THROUGH A SURFACE GANGLIOSIDE (GD3)
Y. Norihisa et al., INCREASED PROLIFERATION, CYTOTOXICITY, AND GENE-EXPRESSION AFTER STIMULATION OF HUMAN PERIPHERAL-BLOOD T-LYMPHOCYTES THROUGH A SURFACE GANGLIOSIDE (GD3), The Journal of immunology, 152(2), 1994, pp. 485-495
Previous studies have suggested that gangliosides have an important ro
le in cell signaling and recognition. However, their specific function
in these processes has not been clearly defined. A mAb, R24, that rea
cts specifically with a cell surface ganglioside (GD3) has been demons
trated to stimulate proliferation of T cells derived from human periph
eral blood. In this study, we have investigated the mechanisms by whic
h the R24 mAb affects T cell functions. We have observed that the R24
mAb stimulates GD3+ T cell proliferation, cytotoxicity, and surface ma
rker expression of IL-2R alpha-chain, IL-2R beta-chain, HLA-DR, CD11a,
and CD11c. Additionally, IFN-gamma activity but not IL-1, IL-2, or IL
-4 activity was present in culture supernatants 72 h after R24 stimula
tion. In some donors, increased IL-6 and TNF-alpha activity also was d
etected after R24 treatment. Furthermore, R24 treatment resulted in tr
anslocation of c-rel, but little or no NFkappaB p50 or p65, from the c
ytoplasm to the nucleus and an increase of NFkappaB binding complexes
containing c-rel and p50. This treatment also caused increased tyrosin
e phosphorylation of specific protein substrates. R24-stimulated incre
ases in proliferation, cytotoxicity, and cell surface protein expressi
on could be blocked by cyclosporin and staurosporin, indicating that c
yclophilin/calcineurin and protein kinase C may be involved in the R24
signaling pathway. Additionally, herbimycin A, a tyrosine kinase inhi
bitor, blocked the R24-stimulated increase in proliferation but not cy
totoxicity at concentrations consistent with specificity for tyrosine
kinases. These results suggest that multiple biochemical pathways are
involved in the activation of human T cells by R24.