The CD4 Receptor: An Indispensable Protein in T Cell Activation and A Promising Target for Immunosuppression

Abstract

The CD4 receptor is the primary entry receptor for the human immunodeficiency virus. Besides this detrimental function, the CD4 receptor is crucial for positive selection and development of CD4+ T cells as well as for proper functioning of the immune system. During T cell activation, the CD4 receptor can fulfill an adhesion function, act as a signaling molecule and enhance the sensitivity of T cells to antigens. In addition, the CD4 receptor was suggested to be involved in differentiation towards the T helper 2 subset and in chemotaxis of T cells. In other types of immune cells, diverging functions are attributed to the CD4 receptor. The immunological importance of the CD4 receptor makes it an interesting target for immunosuppression. This is demonstrated by the immunosuppressive potential of several anti-CD4 monoclonal antibodies. These antibodies may have several modes of action, such as (1) inhibition of CD4+ T cell activation by steric hindrance of the CD4/major histocompatibility complex class II interaction resulting in antigen-specific tolerance, (2) down-modulation of the CD4 receptor, (3) switching from a pro-inflammatory T helper 1 to a more immunomodulatory T helper 2 type immune response, (4) induction of regulatory T cells and enhancement of their activity, or (5) delivery of a negative or attenuated signal into the CD4+ T cell. In addition, medicinal drugs that target CD4 are interesting alternatives for immunosuppressive treatment. The small molecule cyclotriazadisulfonamide (CADA) that down-modulates the CD4 receptor in a unique way by signal peptide-dependent inhibition of ER co-translational translocation is currently under investigation as a novel immunosuppressive drug.