Abnormal adenosine-induced immunosuppression and cAMP metabolism in T lymphocytes of patients with systemic lupus erythematosus.
Normal human T lymphocytes incubated with adenosine (10 muM) for 30 min at 37 degrees C show an increase in the percentage of cells expressing receptors for the Fc portion of IgG (RFc(gamma)) and the OKT8 antigen, while the proportion of OKT4(+) cells decreases. These effects occur exclusively in a subset of T cells with theophylline-resistant sheep erythrocyte receptors (T(R) cells) that is enriched for OKT4(+) cells. Untreated normal T(R) cells express helper/inducer cell activity for T-cell-dependent B-cell differentiation, while adenosine-treated T(R) cells suppress B-cell differentiation. In contrast, in T(R) cells isolated from patients with systemic lupus erythematosus (SLE), adenosine fails to induce immunosuppressor activity or to increase the percentage of OKT8(+) and RFc(gamma) (+) cells. In addition, although incubation of normal T(R) cells with adenosine causes a transient increase in cAMP levels (up to 160% of control within 5 min), in SLE T(R) cells, cAMP levels fall by 50% within 10 min. The photoaffinity label 8-azidoadenosine cyclic [(32)P]monophosphate has been used to show that human T lymphocytes have a single cAMP receptor site that appears to be the regulatory subunit of type I protein kinase. In normal T(R) cells, this receptor becomes occupied in response to adenosine. In contrast, in SLE T(R) cells, no change in cAMP receptor occupancy is detected. Although adenosine has a differential effect on normal and SLE T(R) cells, cAMP derivatives that can traverse the cell membrane (8-bromo- and 8-azidoadenosine cyclic monophosphates) induce an increase in the RFc(gamma) (+) cell subset in both normal and SLE T(R) cells. These results suggest that cAMP mediates the effects of adenosine on cell surface markers of T lymphocytes. The lack of an adenosine receptor-coupled adenylate cyclase activity in SLE T(R) cells may account, in part, for their lack of immunosuppressive activity.
D000241:Adenosine / Q000494:pharmacology*; D000954:Antigens, Surface / Q000032:analysis; D000242:Cyclic AMP / Q000378:metabolism*; D004351:Drug Resistance; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008970:Molecular Weight; D011956:Receptors, Cell Surface / Q000276:immunology; D011953:Receptors, Cyclic AMP / Q000032:analysis; D011961:Receptors, Fc / Q000032:analysis; D011983:Receptors, Purinergic; D013601:T-Lymphocytes / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects; D013806:Theophylline / Q000494:pharmacology
D000954:Antigens, Surface; D011956:Receptors, Cell Surface; D011953:Receptors, Cyclic AMP; D011961:Receptors, Fc; D011983:Receptors, Purinergic; D013806:Theophylline; D000242:Cyclic AMP; D000241:Adenosine