Wingett Denise, Nielson Christopher P
Research Service, Department of Veterans Affairs Medical Center, Boise, Idaho 83702, USA.
J Leukoc Biol. 2003 Oct;74(4):531-41. doi: 10.1189/jlb.0303103. Epub 2003 Jul 15.
T cells are central in the pathogenesis of asthma, and the associated ligand, CD40L, plays an important role by increasing production of immunoglobulin E and inflammatory mediators. beta-Adrenoceptor agonists are commonly used in asthma, although little is known regarding effects on CD40L expression and T cell activation. Here, we demonstrate that cyclic adenosine monophosphate (cAMP) and beta-adrenoceptor agonists differentially regulate CD40L in asthma. cAMP increased naïve T cell CD40L expression in asthmatics (9.8+/-8.5 increase in percent CD40L-positive cells), and expression in control subjects was inhibited (7.1+/-6.0 decrease in percent CD40L-positive cells; P< 0.05). Cell depletion and reconstitution experiments were used to determine that cAMP enhancement of CD40L required cell-to-cell contact with an asthma-associated natural killer (NK) cell subset. The NK cell subset expressed elevated levels of CD95, and in vitro-generated CD95+ NK2 cells also produced similar effects on CD40L expression. Our findings suggest that a subset of NK cells with elevated CD95 expression is associated with asthma and can reverse cAMP inhibitory effects on T cell CD40L with the potential to increase disease exacerbation.
T细胞在哮喘发病机制中起核心作用，其相关配体CD40L通过增加免疫球蛋白E和炎症介质的产生发挥重要作用。β-肾上腺素能受体激动剂常用于治疗哮喘，但其对CD40L表达和T细胞活化的影响知之甚少。在此，我们证明环磷酸腺苷（cAMP）和β-肾上腺素能受体激动剂对哮喘中CD40L的调节存在差异。cAMP增加了哮喘患者初始T细胞CD40L的表达（CD40L阳性细胞百分比增加9.8±8.5），而对照组的表达则受到抑制（CD40L阳性细胞百分比下降7.1±6.0；P<0.05）。通过细胞耗竭和重建实验确定，cAMP增强CD40L需要与哮喘相关的自然杀伤（NK）细胞亚群进行细胞间接触。该NK细胞亚群表达高水平的CD95，体外产生的CD95+NK2细胞对CD40L表达也产生类似影响。我们的研究结果表明，CD95表达升高的NK细胞亚群与哮喘相关，并且可以逆转cAMP对T细胞CD40L的抑制作用，有可能加剧疾病恶化。
