Mechanisms of Peripheral Tolerance Unit, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy.
Mechanisms of Peripheral Tolerance Unit, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy; University of Rome Tor Vergata, Via Cracovia 50, 00133, Rome, Italy.
J Autoimmun. 2023 Jul;138:103051. doi: 10.1016/j.jaut.2023.103051. Epub 2023 May 22.
Tolerogenic dendritic cells play a critical role in promoting antigen-specific tolerance via dampening of T cell responses, induction of pathogenic T cell exhaustion and antigen-specific regulatory T cells. Here we efficiently generate tolerogenic dendritic cells by genetic engineering of monocytes with lentiviral vectors co-encoding for immunodominant antigen-derived peptides and IL-10. These transduced dendritic cells (designated DC) secrete IL-10 and efficiently downregulate antigen-specific CD4 and CD8 T cell responses from healthy subjects and celiac disease patients in vitro. In addition, DC induce antigen-specific CD49bLAG-3 T cells, which display the T regulatory type 1 (Tr1) cell gene signature. Administration of DC resulted in the induction of antigen-specific Tr1 cells in chimeric transplanted mice and the prevention of type 1 diabetes in pre-clinical disease models. Subsequent transfer of these antigen-specific T cells completely prevented type 1 diabetes development. Collectively these data indicate that DC represent a platform to induce stable antigen-specific tolerance to control T-cell mediated diseases.
耐受性树突状细胞通过抑制 T 细胞反应、诱导致病性 T 细胞耗竭和抗原特异性调节性 T 细胞，在促进抗原特异性耐受中发挥关键作用。在这里，我们通过慢病毒载体共转染单核细胞，高效地生成了具有免疫显性抗原衍生肽和 IL-10 的基因工程耐受性树突状细胞（命名为 DC）。这些转导的树突状细胞（DC）分泌 IL-10，并有效地下调来自健康供体和乳糜泻患者的抗原特异性 CD4 和 CD8 T 细胞反应。此外，DC 诱导抗原特异性 CD49bLAG-3 T 细胞，其显示 T 调节型 1（Tr1）细胞基因特征。在嵌合移植小鼠中，给予 DC 导致抗原特异性 Tr1 细胞的诱导，并在临床前疾病模型中预防 1 型糖尿病。随后转移这些抗原特异性 T 细胞完全阻止了 1 型糖尿病的发展。总的来说，这些数据表明，DC 代表了诱导稳定的抗原特异性耐受以控制 T 细胞介导的疾病的平台。
