Hay Joanne, Carter Darrick, Lieber André, Astier Anne L
MRC Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, EH16 4TJ, UK.
Immunology. 2014 Sep 22;144(3):453-60. doi: 10.1111/imm.12391.
The protein CD46 protects cells from complement attack by regulating cleavage of C3b and C3d. CD46 also regulates the adaptive immune response by controlling T cell activation and differentiation. Co-engagement of the T cell receptor and CD46 notably drives T cell differentiation by switching production of IFNγ to secretion of anti-inflammatory IL-10. This regulatory pathway is altered in several chronic inflammatory diseases highlighting its key role for immune homeostasis. The manipulation of the CD46 pathway may therefore provide a powerful means to regulate immune responses. Herein, we investigated the effect of recombinant proteins derived from the fiber knob of the adenovirus serotype 35 (Ad35) that uses CD46 as its entry receptor, on human T cell activation. We compared the effects of Ad35K++, engineered to exhibit enhanced affinity to CD46, and of Ad35K-, mutated in the binding site for CD46. Ad35K++ profoundly affects T cell activation by decreasing the levels of CD46 at the surface of primary T cells, and impairing T cell co-activation, shown by decreased CD25 expression, reduced proliferation and lower secretion of IL-10 and IFNγ. In contrast, Ad35K- acts a potent coactivator of T cells, enhancing T cell proliferation and cytokine production. These data show that recombinant Ad35 proteins are potent modulators of human T cell activation, and support their further development as potential drugs targeting T cell responses. This article is protected by copyright. All rights reserved.
蛋白质CD46通过调节C3b和C3d的裂解来保护细胞免受补体攻击。CD46还通过控制T细胞的激活和分化来调节适应性免疫反应。T细胞受体和CD46的共同参与显著地通过将IFNγ的产生转换为抗炎性IL-10的分泌来驱动T细胞分化。这条调节途径在几种慢性炎症性疾病中发生改变，突出了其对免疫稳态的关键作用。因此，对CD46途径的操控可能提供一种调节免疫反应的有力手段。在此，我们研究了源自腺病毒血清型35（Ad35）纤维结的重组蛋白对人T细胞激活的影响，Ad35以CD46作为其进入受体。我们比较了经工程改造以表现出对CD46增强亲和力的Ad35K++和在CD46结合位点发生突变的Ad35K-的作用。Ad35K++通过降低原代T细胞表面CD46的水平并损害T细胞共激活，从而深刻影响T细胞激活，这表现为CD25表达降低、增殖减少以及IL-10和IFNγ分泌减少。相比之下，Ad35K-作为T细胞的有效共激活剂，增强T细胞增殖和细胞因子产生。这些数据表明重组Ad35蛋白是人类T细胞激活的有效调节剂，并支持它们作为靶向T细胞反应的潜在药物的进一步开发。本文受版权保护。保留所有权利。
