Targeting antigen to dendritic cells in autoimmune diabetes

我们使用嵌合抗体在体内将抗原递送至特定DC亚群。与由DEC 205 + DC引发的应答相比，DCIR 2 + DC能够在自身特异性T细胞中诱导更耐受性的应答，其特征在于即使在这种慢性自身免疫背景下也具有更少的扩增、增加的凋亡和更少的IFN-γ。此外，抗DCIR 2靶向胰岛抗原抑制糖尿病的发展。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更耐受性的DCIR 2 + DC（包括转录调节子zbtb 32）刺激的T细胞中以更高水平表达的基因。 zbtb 32在T细胞中的过表达引起类似于DCIR 2 DC刺激的反应，具有减少的扩增、IFN γ产生和糖尿病发展的抑制。 我们现在正在表征我们用CRISPR直接在NOD背景中产生的NOD zbtb 32敲除小鼠，以确定这种调节剂的丧失对T细胞反应和糖尿病的影响。

We use chimeric antibodies to deliver antigens to specific DC subsets in vivo. Compared to responses elicited by DEC205+ DCs, DCIR2+ DCs are able to induce a more tolerogenic response in self-specific T cells, characterized by less expansion, increased apoptosis and less IFN-gamma even in this chronic autoimmune context. In addition, anti-DCIR2-targeted islet antigen 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 the more tolerogenic DCIR2+ DCs including the transcriptional regulator zbtb32. Overexpression of zbtb32 in T cells elicits a response similar to DCIR2 DC stimulation, with decreased expansion, IFN gamma production and inhibition of diabetes development. We are now characterizing NOD zbtb32 knockout mice we produced with CRISPR directly into the NOD background to determine what effect loss of this regulator has on T cell responses and diabetes.