Holm Are Martin, Aukrust Pål, Aandahl Einar Martin, Müller Fredrik, Taskén Kjetil, Frøland Stig S
Research Institute for Internal Medicine, National Hospital, Oslo, Norway.
J Immunol. 2003 Jun 1;170(11):5772-7. doi: 10.4049/jimmunol.170.11.5772.
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.
普通可变免疫缺陷（CVID）是一组异质性的B细胞缺陷综合征。在CVID患者中，很大一部分存在T细胞异常，提示T细胞介导的对B细胞的刺激受损。基于白细胞介素-10（IL-10）对B细胞功能的重要性以及环磷酸腺苷/蛋白激酶A I型（PKAI）系统参与IL-10的合成，我们检测了CVID患者和对照者T细胞中IL-10的分泌情况，特别关注了cAMP/PKAI系统可能的调节作用。我们的主要发现如下：1）CVID患者经抗CD3和抗CD3/抗CD28激活的T细胞分泌的IL-10少于健康对照者。这一缺陷与T细胞亚群（如CD4(+)/CD8(+)、CD45RA(+)/RO(+)或CD28(-) T细胞）的不同比例无关；2）通过cAMP激动剂8-CPT-cAMP激活PKAI，在患者和对照者中均显著抑制经CD3和CD28激活的T细胞分泌IL-10，但CVID患者对cAMP依赖性抑制的敏感性增加；3）通过Rp-8-Br-cAMPS选择性抑制PKAI，在患者和对照者中均显著增加了经抗CD3和抗CD3/抗CD28刺激的T细胞分泌IL-10。即使在Rp-8-Br-cAMPS最低浓度下，CVID患者IL-10的分泌水平也达到了与对照者相当的水平。我们的研究结果提示CVID患者的T细胞分泌IL-10受损，这表明CVID中T细胞缺陷与B细胞功能受损之间可能存在联系。cAMP/PKAI系统参与这一缺陷提示其可能是CVID治疗性免疫调节的新靶点。
