Impaired secretion of IL-10 by T cells from patients with common variable immunodeficiency--involvement of protein kinase A type I.
Common variable immunodeficiency (CVID) is a heterogeneous group of B cell deficiency syndromes. T cell abnormalities are present in a high proportion of patients with CVID, suggesting impaired T cell-mediated stimulation of B cells. Based on the importance of IL-10 for B cell function and the involvement of the cAMP/protein kinase A type I (PKAI) system in IL-10 synthesis, we examined IL-10 secretion in T cells from CVID patients and controls, particularly focusing on possible modulatory effects of the cAMP/PKAI system. Our main findings were: 1) anti-CD3 and anti-CD3/anti-CD28 activated T cells from CVID patients secreted less IL-10 than healthy controls. This defect was not related to varying proportions of T cell subsets (e.g., CD4(+)/CD8(+), CD45RA(+)/RO(+), or CD28(-) T cells); 2) PKAI activation through the cAMP agonist 8-CPT-cAMP markedly inhibited IL-10 secretion from T cells through CD3 and CD28 activation in both patients and controls, but the sensitivity for cAMP-dependent inhibition was increased in CVID; 3) selective PKAI inhibition by Rp-8-Br-cAMPS markedly increased IL-10 secretion in anti-CD3 and anti-CD3/anti-CD28-stimulated T cells in both patients and controls. Even at the lowest concentrations of Rp-8-Br-cAMPS, IL-10 secretion in CVID patients reached levels comparable to those in controls. Our findings suggest impaired secretion of IL-10 by T cells from CVID patients, suggesting a possible link between T cell deficiency and impaired B cell function in CVID. The involvement of the cAMP/PKAI system in this defect suggests a novel target for therapeutic immunomodulation in CVID.
Holm
Are Martin
AM
Research Institute for Internal Medicine, National Hospital, Oslo, Norway. a.m.holm@klinmed.uio.no
Aukrust
Pål
P
Aandahl
Einar Martin
EM
Müller
Fredrik
F
Taskén
Kjetil
K
Frøland
Stig S
SS
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D017074:Common Variable Immunodeficiency / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D000242:Cyclic AMP / Q000819:agonists / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D015854:Up-Regulation / Q000276:immunology
C105593:8-bromoadenosine-3',5'-cyclic monophosphorothioate; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D021122:Protein Subunits; D013873:Thionucleotides; D016753:Interleukin-10; D015124:8-Bromo Cyclic Adenosine Monophosphate; C053907:8-cyclopentyl-1,3-dimethylxanthine; D013806:Theophylline; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D017493:Leukocyte Common Antigens