Recombinant Ad35 adenoviral proteins as potent modulators of human T-cell activation

Abstract

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 interferon-γ to secretion of anti-inflammatory interleukin-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 fibre 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 Ad35K̶  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 coactivation, shown by decreased CD25 expression, reduced proliferation and lower secretion of interleukin-10 and interferon-γ. In contrast, Ad35K̶  acts a potent co-activator 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.