Targeting antigen to dendritic cells in autoimmune diabetes

我们在体内使用嵌合抗体将抗原递送到特定的DC亚群。与DEC205+DC相比，DCIR2+DC能够在自身特异性T细胞中诱导更多的耐受性反应，其特征是即使在这种慢性自身免疫的情况下，也具有较少的扩增、较多的凋亡和较少的干扰素-γ。此外，抗DCIR2靶向的胰岛抗原可抑制糖尿病的发展。通过比较体内用DEC205+或DCIR2+DC刺激后早期的β细胞特异性T细胞的基因表达，我们已经确定了在更具耐受性的DCIR2+DC刺激的T细胞中高水平表达的基因，包括转录调节因子zbtb32。在T细胞中过表达zbtb32引起类似于DCIR2 DC刺激的反应，减少了扩张，干扰素γ的产生，并抑制了糖尿病的发展。我们现在正在鉴定我们用CRISPR产生的NOD zbtb32基因敲除小鼠，直接进入NOD背景，以确定这种调节因子的缺失对T细胞反应和糖尿病有什么影响。

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.