Immunosine (7-thia-8-oxoguanosine) acts as a cofactor for proliferation of T cells.
Immunosine (7-thia-8-oxoguanosine) is a novel guanosine analogue showing immunostimulatory activity both in vivo and in vitro. This compound acts on different components of the immune system including B cells, natural killer (NK) cells and antigen-presenting cells (APC). However, its influence on functions of T cells is poorly understood. In this work we studied the effect of immunosine on proliferation of total rat splenocytes and purified T cells triggered by different mitogens and the mechanisms involved. The results demonstrate that immunosine significantly stimulates proliferation of T cells. The effect was dose-dependent and also depended on concentrations of specific stimulators. Maximal stimulation was seen using 250 microM immunosine. The stimulatory effect of immunosine on lymphocyte proliferation triggered by Concanavalin A (Con A) correlated with increased interleukin 2 (IL-2) production and upregulation of the IL-2 receptor alpha (IL-2Ralpha) expression. The dependency of T-cell proliferation on IL-2/IL-2R was confirmed using neutralizing anti-IL-2Ralpha monoclonal antibodies (mAbs). Higher concentrations of immunosine in the presence of optimal concentrations of Con A (5 microg/mL) inhibited proliferation of T cells. A similar stimulatory effect of immunosine on proliferation of purified T cells and IL-2 production was observed using an anti-T-cell receptor (TCR) mAb and a combination of anti-TCR mAb and IL-2. However, the guanosine analogue did not significantly modulate proliferation of T cells triggered by IL-2 alone. When the combination of phorbol myristate acetate (PMA) and ionomycin was used for T-cell stimulation different results were obtained. Under lower cell stimulation immunosine significantly potentiated T-cell proliferation, expression of IL-2Ralpha and IL-2 production. In the presence of suboptimal stimulation the compound stimulated T-cell proliferation and IL-2Ralpha expression, whereas under maximal stimulation an enhancing effect on IL-2 production was seen. Since direct stimulatory effect of immunosine on T-cell growth in culture was rather weak it can be postulated that the compound acts as a cofactor for T-lymphocyte proliferation.
Colić
M
M
Institute of Medical Research, MMA, Crnotravska 17, 11002 Belgrade, Yugoslavia. vmaimi@eunet.yu
Jandrić
D
D
Gasić
S
S
Vucević
D
D
Popović
P
P
Medić-Mijacević
L
L
Rakić
L
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit; D008297:Male; D008934:Mitogens / Q000494:pharmacology; D051381:Rats; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000276:immunology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D008934:Mitogens; D018123:Receptors, Interleukin; D003208:Concanavalin A; D006151:Guanosine; C061136:isatoribine