Hirai Toshihito, Ramos Teresa L, Lin Po-Yu, Simonetta Federico, Su Leon L, Picton Lora K, Baker Jeanette, Lin Jian-Xin, Li Peng, Seo Kinya, Lohmeyer Juliane K, Bolivar-Wagers Sara, Mavers Melissa, Leonard Warren J, Blazar Bruce R, Garcia K Christopher, Negrin Robert S
Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University, Stanford, California, USA.
Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.
J Clin Invest. 2021 Apr 15;131(8). doi: 10.1172/JCI139991.
Adoptive transfer of Tregs has been shown to improve alloengraftment in animal models. However, it is technically challenging to expand Tregs ex vivo for the purpose of infusing large numbers of cells in the clinic. We demonstrate an innovative approach to engineering an orthogonal IL-2/IL-2 receptor (IL-2R) pair, the parts of which selectively interact with each other, transmitting native IL-2 signals, but do not interact with the natural IL-2 or IL-2R counterparts, thereby enabling selective stimulation of target cells in vivo. Here, we introduced this orthogonal IL-2R into Tregs. Upon adoptive transfer in a murine mixed hematopoietic chimerism model, orthogonal IL-2 injection significantly promoted orthogonal IL-2R+Foxp3GFP+CD4+ cell proliferation without increasing other T cell subsets and facilitated donor hematopoietic cell engraftment followed by acceptance of heart allografts. Our data indicate that selective target cell stimulation enabled by the engineered orthogonal cytokine receptor improves Treg potential for the induction of organ transplantation tolerance.
在动物模型中，过继性转移调节性T细胞（Tregs）已被证明可改善同种异体移植。然而，为了在临床上输注大量细胞而在体外扩增Tregs在技术上具有挑战性。我们展示了一种创新方法，用于构建一对正交的白细胞介素-2/白细胞介素-2受体（IL-2/IL-2R），其各部分选择性地相互作用，传递天然IL-2信号，但不与天然IL-2或IL-2R对应物相互作用，从而能够在体内选择性刺激靶细胞。在此，我们将这种正交IL-2R引入Tregs。在小鼠混合造血嵌合模型中进行过继性转移后，注射正交IL-2可显著促进正交IL-2R+Foxp3GFP+CD4+细胞增殖，而不会增加其他T细胞亚群，并促进供体造血细胞植入，随后接受心脏同种异体移植。我们的数据表明，工程化的正交细胞因子受体实现的选择性靶细胞刺激可提高Tregs诱导器官移植耐受的潜力。
