DEC-205 and Autoimmunity

Nussenzweig, Michel

Abstract

Self-reactive T lymphocytes are normally deleted centrally or silenced in the periphery. However, anti-self reactivity is a characteristic pathologic feature of a number of autoimmune disorders. Elegant studies with transgenic mice, and purified cells in tissue culture have demonstrated that deletion of auto-reactive T cells in the thymus is likely to be triggered by thymic medullary dendritic cells. By contrast, the thymic epithelium appears to be predominantly involved in positive selection. But despite the central role of dendritic cells and thymic epithelial cells in the establishment and maintenance of self tolerance, and the requirement that these two cell types process a variety of different self and foreign antigens, neither cell type has been shown to express specific receptors for antigen capture. We have recently cloned a 205Kd candidate receptor for antigen capture expressed by dendritic cells and thymic epithelial cells (DEC-205). The new receptor is a membrane anchored protein which has ten separate Ca++ dependent carbohydrate recognition domains suggesting that it will recognize specific carbohydrate structures. Using anti-receptor antibodies as probes, we have shown that antigens bound to DEC-205 were efficiently processed and presented to T cells. However, the natural ligands of DEC- 205 remain to be defined. The long range goal of the proposed research is to elucidate the molecular requirements for ligand binding by DEC-205, and to understand the role of this new receptor in induction and preservation of tolerance. The working hypothesis is that DEC-25 binds to carbohydrate structures, and that antigens bearing these carbohydrates will be captured by DEC-205 for processing and presentation. The first part of the proposed project will be to establish the ligand binding specificity of DEC-205. For this purpose we will produce recombinant DEC-205, and perform binding studies as has been done for related receptors. In the second part of the project we will explore the effects of a DEC-205 mutation on T cell development and the immune responses in vivo. Finally the sequence of the human counterpart of mouse DEC-205 will be determined and molecular probes produced from the cDNA will be investigated as markers for human dendritic cells in normal subjects, and in patients with autoimmune diseases. These studies have significant implications for understanding how auto-antigens can produce tolerance, and together with other components of the proposed program will identify new pathways for the induction of tolerance.