Regulatory T cells engineered with TCR signaling-responsive IL-2 nanogels suppress alloimmunity in sites of antigen encounter.
Regulatory T cells engineered with TCR signaling-responsive IL-2 nanogels suppress alloimmunity in sites of antigen encounter.
复制标题
DOI：
10.1126/scitranslmed.aaw4744
复制
发表时间：
2020-11-11
影响因子：
17.1
通讯作者：
Azzi JR
中科院分区：
文献类型：
--
作者：
Eskandari SK;Sulkaj I;Melo MB;Li N;Allos H;Alhaddad JB;Kollar B;Borges TJ;Eskandari AS;Zinter MA;Cai S;Assaker JP;Choi JY;Al Dulaijan BS;Mansouri A;Haik Y;Tannous BA;van Son WJ;Leuvenink HGD;Pomahac B;Riella LV;Tang L;Seelen MAJ;Irvine DJ;Azzi JR
体外扩增调节性T细胞(Treg)的过继细胞转移在自身免疫和同种异体免疫的动物模型中显示出巨大的潜力。然而，这种Treg疗法在临床上的有效转化一直很缓慢。由于Treg动态平衡需要持续的T细胞受体(TCR)连接和外源性IL-2，一些研究人员已经探索了使用小剂量IL-2注射来增加内源性Treg反应。然而，全身IL-2免疫治疗也会导致细胞毒性T淋巴细胞和自然杀伤(NK)细胞的激活，导致不良的治疗结果。在这里，我们描述了一种药物传递平台，它可以被设计成在TCR依赖的激活反应中用IL-2自动刺激Tregs，从而在抗原相遇的位置激活这些细胞。为此，蛋白质纳米凝胶(NGS)由可切割的双-N-羟基琥珀酰亚胺交联剂和IL-2/Fc融合蛋白(IL-2)合成，在还原条件下释放IL-2，通过T细胞受体在T细胞表面发现释放IL-2的颗粒。与未修饰的Tregs或全身IL-2刺激的Tregs相比，表面结合了IL-2的Tregs具有优先的同种异体移植物保护作用。在小鼠和人源化小鼠同种异体移植模型中，我们证明了携带IL-2的小鼠和人NG修饰的Tregs在抑制同种异体免疫方面比传统的Tregs表现得更好。总而言之，这项研究中提出的技术具有改善Treg转移治疗的潜力，因为它能够调节IL-2的时空供应给抗原诱导的Treg。氧化还原敏感的细胞因子包裹在调节性T细胞上，促进排斥区域的局部免疫调节。
Adoptive cell transfer of ex vivo-expanded regulatory T cells (Treg) has shown immense potential in animal models of auto- and allo-immunity. However, the effective translation of such Treg therapies to the clinic has been slow. As Treg homeostasis is known to require continuous T-cell receptor (TCR) ligation and exogenous interleukin (IL-)2, some investigators have explored the use of low-dose IL-2 injections to increase endogenous Treg responses. Systemic IL-2 immunotherapy, however, can also lead to the activation of cytotoxic T lymphocytes and natural killer (NK) cells, causing adverse therapeutic outcomes. Here, we describe a drug-delivery platform which can be engineered to autostimulate Tregs with IL-2 in response to TCR-dependent activation and thus activate these cells in sites of antigen encounter. To this end, protein nanogels (NGs) were synthesized with cleavable bis-N-hydroxy succinimide crosslinkers and IL-2/Fc fusion (IL-2) proteins to form particles that release IL-2 under reducing conditions, as found at the surface of T cells receiving stimulation through the T-cell receptor. Tregs surface-conjugated with IL-2 NGs were found to have preferential, allograft-protective effects relative to unmodified Tregs or Tregs stimulated with systemic IL-2. We demonstrate that murine and human NG-modified Tregs carrying an IL-2 cargo perform better than conventional Tregs in suppressing alloimmunity in murine and humanized mouse allotransplantation models. In all, the technology presented in this study has the potential to improve Treg transfer therapy by enabling the regulated spatiotemporal provision of IL-2 to antigen-primed Tregs. Redox-sensitive cytokine cargos backpacked on regulatory T cells promote local immune regulation in areas of rejection.
登录
查看更多内容
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
4.4
作者：
Burchill, Matthew A.;Yang, Jianying;Farrar, Michael A.
通讯作者：
Farrar, Michael A.
影响因子：
64.8
作者：
Austrup, F;Vestweber, D;Hamann, A
通讯作者：
Hamann, A
影响因子：
30.5
作者：
Grohmann, U;Orabona, C;Puccetti, P
通讯作者：
Puccetti, P
影响因子：
48
作者：
de Chaumont, Fabrice;Dallongeville, Stephane;Olivo-Marin, Jean-Christophe
通讯作者：
Olivo-Marin, Jean-Christophe