Abnormal adenosine-induced immunosuppression and cAMP metabolism in T lymphocytes of patients with systemic lupus erythematosus

AUTOR(ES)

Mandler, Raya

RESUMO

Normal human T lymphocytes incubated with adenosine (10 μM) for 30 min at 37°C show an increase in the percentage of cells expressing receptors for the Fc portion of IgG (RFcγ) 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 (TR cells) that is enriched for OKT4+ cells. Untreated normal TR cells express helper/inducer cell activity for T-cell-dependent B-cell differentiation, while adenosine-treated TR cells suppress B-cell differentiation. In contrast, in TR cells isolated from patients with systemic lupus erythematosus (SLE), adenosine fails to induce immunosuppressor activity or to increase the percentage of OKT8+ and RFcγ+ cells. In addition, although incubation of normal TR cells with adenosine causes a transient increase in cAMP levels (up to 160% of control within 5 min), in SLE TR cells, cAMP levels fall by 50% within 10 min. The photoaffinity label 8-azidoadenosine cyclic [32P]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 TR cells, this receptor becomes occupied in response to adenosine. In contrast, in SLE TR cells, no change in cAMP receptor occupancy is detected. Although adenosine has a differential effect on normal and SLE TR cells, cAMP derivatives that can traverse the cell membrane (8-bromo- and 8-azidoadenosine cyclic monophosphates) induce an increase in the RFcγ+ cell subset in both normal and SLE TR 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 TR cells may account, in part, for their lack of immunosuppressive activity.

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