Targeting antigen to dendritic cells in autoimmune diabetes

DEC-205是一种由独特的CD8 α +树突状细胞亚群表达的内吞受体。在免疫正常小鼠中，通过嵌合抗体构建将蛋白靶向DEC-205可导致抗原特异性CD4+和CD8+ T细胞克隆性缺失或激活。在NOD小鼠（一种自身免疫性糖尿病小鼠模型）中，β细胞特异性CD8+ T细胞可通过抗dec抗原治疗被耗尽（Mukhopadhaya a, et al.）。PNAS 2008)。利用DEC-205靶向，我们现在已经确定，在自身免疫性NOD小鼠中，CD8 dc不能诱导CD4+ T细胞耐受。

DEC-205 is an endocytic receptor expressed by a distinct CD8 alpha+ dendritic cell subpopulation. Targeting of proteins to DEC-205 through chimeric antibody constructs causes clonal deletion or anergy of antigen-specific CD4+ and CD8+ T cells in immunologically normal mice. In NOD mice, a mouse model for autoimmune diabetes, beta cell-specific CD8+ T cells can be depleted by anti-DEC antigen treatment (Mukhopadhaya A, et al. PNAS 2008). Using DEC-205 targeting, we have now determined that in autoimmune NOD mice, CD8 DCs are not able to induce CD4+ T cell tolerance. NOD mice were injected with BDC2.5 T cell receptor (TCR) transgenic CD4+ T cells that recognize the beta cell antigen chromogranin A, followed by treatment with anti-DEC-205 attached to a BDC mimeotope peptide. Three days after anti-DEC-205 treatment, BDC T cells had proliferated in lymphoid organs, similar to results in normal mice. However, ten days after treatment with anti-DEC-205, when T cells are deleted in normal mice, antigen-specific cells remained in the autoimmune mice and were not anergic (they retained capacity to produce interferon gamma). In addition, no increase in regulatory T cells was observed. Therefore, antigen targeted to NOD CD8 DCs does not induce deletion, anergy or regulatory T cells (the 3 main mechanisms of peripheral T cell tolerance). We are interested in what immune pathways may be important for restoring tolerance in this setting. CD40/CD40L interactions are one pathway that may be important: when a blocking antibody specific for anti-CD40L was given with anti-DEC-205 antigen, T cell responses were more tolerogenic. CD11b+ dendritic cells express DCIR2 on their surface, and antibodies specific for DCIR2 can be used to target antigens to this DC subset. We are now measuring BDC2.5 TCR transgenic T cell responses after stimulation in vivo with anti-DCIR2-targeted BDC peptide in NOD mice. We are also testing whether this antibody-antigen combination can alter diabetes development.