Targeting antigen to dendritic cells in autoimmune diabetes

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，我们先前已经证明β细胞特异性CD 8 + T细胞可以通过抗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。相反，将同源抗原靶向DEC 205 + DC诱导自身反应性CD 4 T细胞中的扩增和IFN γ产生。我们已经表明，CD 40/CD 40 L相互作用是在这种情况下重要的一种途径：当抗CD 40 L特异性阻断抗体与抗DEC-205抗原一起给予时，T细胞应答更具耐受性（较少扩增和IFN γ产生）。这项研究发表在今年的《白细胞生物学杂志》上。 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。我们已经测量了用抗DCIR 2靶向BDC肽体内刺激后NOD小鼠中的BDC2.5 TCR转基因T细胞应答。与由DEC 205 + DC引起的应答相反，DCIR 2 + DC能够诱导更具致耐受性的应答，其特征在于更少的扩增、增加的凋亡和更少的IFN-γ，即使在这种慢性自身免疫背景下。此外，抗DCIR 2靶向的BDC肽抑制糖尿病的发展。通过比较用DEC 205+或DCIR 2 + DC体内刺激后早期β细胞特异性T细胞中的基因表达，我们已经鉴定了在用DCIR 2 + DC刺激的T细胞中以更高水平表达的基因。

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, we previously have shown that 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. Instead targeting cognate antigen to DEC205+ DCs induces expansion and IFN gamma production in the autoreactive CD4 T cells. We have shown that CD40/CD40L interactions are one pathway that is important in this setting: 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 was published this year in the Journal of Leukocyte Biology. CD11b+ dendritic cells express DCIR2 on their surface, and antibodies specific for DCIR2 can be used to target antigens to this DC subset. We have measured BDC2.5 TCR transgenic T cell responses in NOD mice after stimulation in vivo with anti-DCIR2-targeted BDC peptide. In contrast to the responses elicited by DEC205+ DCs, DCIR2+ DCs are able to induce a more tolerogenic response, characterized by less expansion, increased apoptosis and less IFN-gamma even in this chronic autoimmune context. In addition, anti-DCIR2-targeted BDC peptide inhibits diabetes development. By comparing gene expression in beta cell-specific T cells early after in vivo stimulation with either DEC205+ or DCIR2+ DCs, we have identified genes that are expressed at higher levels in T cells stimulated with DCIR2+ DCs.