Increased activation of protein kinase a type I contributes to the T cell deficiency in common variable immunodeficiency

The molecular mechanisms underlying the T cell dysfunction often present in common variable immunodeficiency (CVI) are not established, cAMP-dependent protein kinase A type I (PKAI) is an important inhibitor of T cell prolife ration after Ag stimulation. We therefore investigated the possibility that activation of PKAI may be involved in the development of T cell dysfunctio n in CVI, An exogenously added PKAI-selective antagonist (Rp-8-Br-cAMPS) in duced a significant increase in anti-CD3-stimulated PBMC proliferation in 2 0 CVI patients compared with no effect in 15 controls. Purified T cells fro m 7 CVI patients with strictly defined T cell deficiency had elevated endog enous cAMP levels compared with controls. Treatment of T cells from these C VI patients with Rp-8-bromo-cAMP-phosphorothioate markedly improved anti-CD 3-stimulated proliferation (up to 3.7-fold), particularly in CD4(+) lymphoc ytes, reaching: proliferation levels comparable to control values. No effec t of cAMP antagonist on T cell proliferation was seen in controls. In these CVI patients, cAMP antagonist also increased IL-2 production in anti-CD3-s timulated T cells, However, exogenously added IL-2 at concentrations compar able to the achieved increase in IL-2 levels after addition of cAMP antagon ist had no effect on T cell proliferation. Furthermore, the stimulatory eff ects of exogenously added IL-2 at higher concentrations and cAMP antagonist on T cell proliferation were additive. Our findings indicate that increase d PKAI activation may be an important molecular basis for the T cell defect in CVI and suggest that the cAMP/PKAI system may be a potential molecular target for immunomodulating therapy in these patients.