Targeting antigen to dendritic cells in autoimmune diabetes

DEC-205是由不同的CD 8 α +树突细胞亚群表达的内吞受体。通过嵌合抗体构建体将蛋白质靶向DEC-205导致免疫正常小鼠中抗原特异性CD 4+和CD 8 + T细胞的克隆缺失或无反应性。在NOD小鼠（一种自身免疫性糖尿病的小鼠模型）中，β细胞特异性CD 8 + T细胞可通过抗DEC抗原治疗而耗尽（Mukhopadhaya A等人，PNAS 2008）。使用DEC-205靶向，我们现在已经确定在自身免疫NOD小鼠中，CD 8 DC不能诱导CD 4 + T细胞耐受。靶向NOD CD 8 DC的抗原不诱导缺失、无反应性或调节性T细胞（外周T细胞耐受的3种主要机制），而是诱导T细胞中的扩增和IFN γ产生。我们感兴趣的是，在这种情况下，哪些免疫途径对恢复耐受性可能很重要。CD 40/CD 40 L相互作用是一种可能很重要的途径：当抗CD 40 L特异性阻断抗体与抗DEC-205抗原一起给予时，T细胞应答更具致耐受性（较少扩增和IFN γ产生）。 这项工作目前正在审查之中。 CD 11b+树突状细胞在其表面上表达DCIR 2，并且DCIR 2特异性抗体可用于将抗原靶向该DC亚群。我们现在测量在NOD小鼠中用抗DCIR 2靶向BDC肽体内刺激后的BDC2.5 TCR转基因T细胞应答。我们还在测试这种抗体-抗原组合是否可以改变糖尿病的发展。 此外，我们还比较了用DEC 205+或DCIR 2 + DC体内刺激后β细胞特异性T细胞中的基因表达。

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. Antigen targeted to NOD CD8 DCs does not induce deletion, anergy or regulatory T cells (the 3 main mechanisms of peripheral T cell tolerance), but instead induces expansion and IFN gamma production in the T cells. 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 (less expansion and IFN gamma production). This work is now under review. 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. In addition, we have compared gene expression in beta cell-specific T cells after in vivo stimulation with either DEC205+ or DCIR2+ DCs.