CD83 AS A MOLECULAR SWITCH FOR THE INDUCTION OF REGULATORY (IMMUNOSUPPRESSIVE) T-CELLS

摘要

The present invention makes use of the role of the surface protein CD83 in the induction of regulatory T cells (Tregs). The present invention relates to means and methods for overexpressing CD83 as well as methods for identifying compounds that are interacting with the CD83 polypeptide, and to compounds capable of functioning as immunomodulators in mammals, in particular humans. In addition, the present invention relates to methods of treatment of a subject, in particular a human, suffering from an undesired immunoreaction. The transmembrane protein CD83 has been initially described as a maturation marker for dendritic cells (DCs). Moreover, there is increasing evidence that CD83 also regulates B cell function, thymic T cell maturation and peripheral T cell activation. Here, we show that CD83 expression confers immunosuppressive function to CD4⁺ T cells. CD83 mRNA is differentially expressed in naturally occurring CD4⁺CD25⁺ regulatory T (Treg) cells and upon activation these cells rapidly express large amounts of surface CD83. Transduction of naive CD4⁺CD25^- T cells with CD83 encoding retroviruses induces a regulatory phenotype in vitro, which is accompanied by the induction of Foxp3. Functional analysis of CD83-transduced T cells in vivo demonstrates that these CD83⁺Foxp3⁺ T cells are able to interfere with the effector phase of severe contact hypersensitivity (CHS) reaction of the skin. Moreover, adoptive transfer of these cells prevents the paralysis associated with experimental autoimmune encephalomyelitis (EAE), suppresses pro-inflammatory cytokines IFN- and IL- 17 and increases anti-inflammatory IL-IO in recipient mice. Together, our data provides the first evidence that CD83 expression can contribute to the immunosuppressive function of CD4⁺ T cells in vivo.