Increased Activation of Protein Kinase A Type I Contributes to the T Cell Deficiency in Common Variable Immunodeficiency

• Published in: The Journal of immunology (1950) Vol. 162; no. 2; pp. 1178 - 1185
• Main Authors: Aukrust, Pal, Aandahl, Einar Martin, Skalhegg, Bjorn S, Nordoy, Ingvild, Hansson, Vidar, Tasken, Kjetil, Froland, Stig S, Muller, Fredrik
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.01.1999
• Subjects: Adult; Aged; CD3 Complex - immunology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Separation; Cell-Free System - metabolism; Common Variable Immunodeficiency - enzymology; Common Variable Immunodeficiency - immunology; Cyclic AMP - agonists; Cyclic AMP - analogs & derivatives; Cyclic AMP - antagonists & inhibitors; Cyclic AMP - pharmacology; Cyclic AMP-Dependent Protein Kinases - metabolism; Drug Synergism; Enzyme Activation - drug effects; Enzyme Activation - immunology; Female; Humans; Immune Sera - pharmacology; Interleukin-2 - metabolism; Interleukin-2 - pharmacology; Lymphocyte Activation - drug effects; Male; Middle Aged; T-Lymphocytes - drug effects; T-Lymphocytes - enzymology; T-Lymphocytes - immunology; Thionucleotides - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.162.2.1178

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 proliferation after Ag stimulation. We therefore investigated the possibility that activation of PKAI may be involved in the development of T cell dysfunction in CVI. An exogenously added PKAI-selective antagonist (Rp-8-Br-cAMPS) induced a significant increase in anti-CD3-stimulated PBMC proliferation in 20 CVI patients compared with no effect in 15 controls. Purified T cells from 7 CVI patients with strictly defined T cell deficiency had elevated endogenous cAMP levels compared with controls. Treatment of T cells from these CVI patients with Rp-8-bromo-cAMP-phosphorothioate markedly improved anti-CD3-stimulated proliferation (up to 3.7-fold), particularly in CD4+ lymphocytes, reaching proliferation levels comparable to control values. No effect 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-stimulated T cells. However, exogenously added IL-2 at concentrations comparable to the achieved increase in IL-2 levels after addition of cAMP antagonist had no effect on T cell proliferation. Furthermore, the stimulatory effects of exogenously added IL-2 at higher concentrations and cAMP antagonist on T cell proliferation were additive. Our findings indicate that increased 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.