Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA 98126, USA.
Center for Systems Immunology, Benaroya Research Institute, Seattle, WA 98126, USA.
Cell Rep. 2024 Nov 26;43(11):114938. doi: 10.1016/j.celrep.2024.114938. Epub 2024 Nov 2.
Interleukin-2 (IL-2) variants with increased CD25 dependence that selectively expand Foxp3 regulatory T (T) cells are in clinical trials for treating inflammatory diseases. Using an Fc-fused IL-2 mutein (Fc.IL-2 mutein) we developed that prevents diabetes in non-obese diabetic (NOD) mice, we show that Fc.IL-2 mutein induced an activated T population with elevated proliferation, a transcriptional program associated with Stat5- and T cell receptor-dependent gene modules, and high IL-10 and CTLA-4 expression. Increased IL-10 signaling limited surface major histocompatibility complex class II upregulation during conventional dendritic cell (cDC) maturation, while increased CTLA-4-dependent transendocytosis led to the transfer of CD80 and CD86 co-stimulatory ligands from maturing cDCs to T cells. In NOD mice, Fc.IL-2 mutein treatment promoted the suppression of cDCs in the inflamed pancreas and pancreatic lymph nodes, resulting in T cell anergy. Thus, IL-2 mutein-expanded T cells have enhanced functional properties and restrict cDC function, offering promise for targeted immunotherapy use in autoimmune disease.
白细胞介素-2（IL-2）变体与增加的 CD25 依赖性，选择性地扩展 Foxp3 调节性 T（T）细胞，正在临床试验中用于治疗炎症性疾病。我们使用开发的一种融合了 Fc 的 IL-2 突变体（Fc.IL-2 mutein），该突变体可预防非肥胖型糖尿病（NOD）小鼠的糖尿病，我们发现 Fc.IL-2 mutein 诱导了一种具有高增殖活性的激活 T 细胞群体，该群体与 Stat5 和 T 细胞受体依赖性基因模块相关联，并高表达 IL-10 和 CTLA-4。增加的 IL-10 信号在常规树突状细胞（cDC）成熟过程中限制了表面主要组织相容性复合体 II 的上调，而增加的 CTLA-4 依赖性跨细胞内吞作用导致成熟 cDC 向 T 细胞转移共刺激配体 CD80 和 CD86。在 NOD 小鼠中，Fc.IL-2 mutein 治疗促进了炎症胰腺和胰腺淋巴结中 cDC 的抑制，导致 T 细胞失能。因此，IL-2 突变体扩展的 T 细胞具有增强的功能特性，并限制 cDC 的功能，为自身免疫性疾病的靶向免疫治疗提供了希望。
