Swainsonine, an inhibitor of mannosidase II during glycoprotein processing, enhances concanavalin A-induced T cell proliferation and interleukin 2 receptor expression exclusively via the T cell receptor complex.
The T cell receptor (TCR) is a disulfide-linked heterodimer consisting of both complex and high-mannose types of N-linked oligosaccharides. The objective of the present investigation was to examine the effect of altered oligosaccharide structure on the expression and function of the TCR. Human mononuclear lymphocytes (MNL) were treated with castanospermine (CAST) or swainsonine (SW), inhibitors of glucosidase I or mannosidase II, respectively. Treatment with these inhibitors does not prevent glycosylation, but results in synthesis of glycoproteins with high-mannose or hybrid types of oligosaccharides. Treatment of MNL with CAST (1000-10 microM) or SW (100-1 microM) for up to 72 hr had no effect on cell surface expression of of the TCR. SW potentiated Con A-induced T cell proliferation without effecting anti-CD3 (OKT3) or alloantigen-induced proliferation. CAST had no effect on Con A, anti-CD3, or alloantigen-induced T cell proliferation. The T cell proliferative response to Con A in the presence of SW was completely eliminated in the presence of monoclonal anti-TCR antibodies. Monoclonal anti-CD2, -CD3, -CD4, -CD8, or isotypic control monoclonal antibodies had no effect on SW enhancement of T cell proliferation. SW treatment potentiated Con A-induced MNL expression of both the alpha and beta subunits of the IL 2R. This effect was also specifically blocked by anti-TCR monoclonal antibodies. These results demonstrate that selective changes in the glycosylation state of the TCR complex can alter mitogen recognition and subsequent cellular activation.
Bowlin
T L
TL
Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Schroeder
K K
KK
Fanger
B O
BO
D000470:Alkaloids / Q000008:administration & dosage*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D017252:CD3 Complex; D003208:Concanavalin A / Q000008:administration & dosage; D004357:Drug Synergism; D006031:Glycosylation; D006801:Humans; D066298:In Vitro Techniques; D007212:Indolizines / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008361:Mannosidases / Q000037:antagonists & inhibitors*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism; D008970:Molecular Weight; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000737:chemistry / Q000276:immunology*; D017026:Swainsonine; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D054836:Indolizidines
D000470:Alkaloids; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D003208:Concanavalin A; D007212:Indolizines; D008361:Mannosidases; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D017026:Swainsonine; C038829:mannosyl-oligosaccharide 1,3 - 1,6-alpha-mannosidase; C037806:castanospermine; D054836:Indolizidines