ELEVATION OF INTRACELLULAR CYCLIC-AMP INDUCES AN ANERGIC-LIKE STATE IN TH1 CLONES

Because elevated intracellular cAMP suppresses T cell receptor (TCR)-m ediated effector activity and/or proliferation ill response to antigen but does not always affect IL-2-stimulated proliferation, the effects of cAMP on a T lymphocyte response to antigen resemble antigen-induce d anerby. To test the hypothesis that elevated cAMP induces anergy in T lymphocytes, we have precultured murine Th1 clones responsive to por cine myelin basic protein (PMBP) with dibutyryl cyclic AMP (dbcAMP) or forskolin and subsequently removed the dbcAMP or forskolin and measur ed the proliferative response of the clones to antigen and antigen-pre senting cells (APC) in the presence or absence of exogenously added in terleukin-2 (IL-2). Cells precultured with dbcAMP or forskolin for 3 d ays did not proliferate or produce IL-2 in response to antigen and APC , but did proliferate to antigen and APC in the presence of IL-2, Cell s that had not been stimulated recently with antigen/APC or IL-2 were not affected by dbcAMP, while cells stimulated recently with antigen A PC: and IL-2 were susceptible to the anergizing effect of dbcAMP. Thes e observations support the hypothesis that elevation in intracellular cAMP in antigen-activated Th1 clones, prior to subsequent culture with antigen, induces a state of anergy. (C) 1996 Academic Press, Inc.