Signal Transduction through CD4 Receptors: Stimulatory Versus Inhibitory Activity is Regulated by CD4 Proximity to the CD3/T Cell Receptor

摘要

The binding of antibody to the CD4 molecule inhibits mobilization of cytoplasmic free calcium (Ca2+i) in response to CD3 cross-linking on resting T cells. Similarly, when CD3 and CD4 are independently and simultaneously cross-linked, calcium mobilization is inhibited when compared to that induced by cross-linking CD3 alone. In contrast, when anti-CD4 and anti-CD3 are cross-linked together, calcium mobilization is substantially higher than from CD3 cross-linking alone. A heteroconjugate consisting of covalently bound CD3 and CD4 monoclonal antibodies (mAb) retains the ability to mobilize Ca2+i in CD4 cells at protein concentrations approximately two orders of magnitude lower than the free CD3 mAb, and the activity of the heteroconjugate is inhibitable by free CD4 mAb. The CD3/CD4 heteroconjugate co-modulates the CD3 and CD4 receptors, indicating that the heteroconjugate is not simply anchoring the T cell receptor to the T cell surface like anti-CD3 on a solid surface. These results suggest that CD4 plays an active role in signal transduction when brought into close physical proximity to the CD3/T cell receptor complex during major histocompatibility complex class II-restricted antigen presentation. Keywords: Biochemistry; Cytochemistry; Reprints. (kt)