Moderna, Inc, Cambridge, MA, 02139, USA.
Nat Commun. 2022 Jul 5;13(1):3866. doi: 10.1038/s41467-022-31130-9.
Interleukin-2 (IL-2) is critical for regulatory T cell (Treg) function and homeostasis. At low doses, IL-2 can suppress immune pathologies by expanding Tregs that constitutively express the high affinity IL-2Rα subunit. However, even low dose IL-2, signaling through the IL2-Rβ/γ complex, may lead to the activation of proinflammatory, non-Treg T cells, so improving specificity toward Tregs may be desirable. Here we use messenger RNAs (mRNA) to encode a half-life-extended human IL-2 mutein (HSA-IL2m) with mutations promoting reliance on IL-2Rα. Our data show that IL-2 mutein subcutaneous delivery as lipid-encapsulated mRNA nanoparticles selectively activates and expands Tregs in mice and non-human primates, and also reduces disease severity in mouse models of acute graft versus host disease and experimental autoimmune encephalomyelitis. Single cell RNA-sequencing of mouse splenic CD4 T cells identifies multiple Treg states with distinct response dynamics following IL-2 mutein treatment. Our results thus demonstrate the potential of mRNA-encoded HSA-IL2m immunotherapy to treat autoimmune diseases.
白细胞介素 2（IL-2）对于调节性 T 细胞（Treg）的功能和稳态至关重要。在低剂量下，IL-2 通过扩展高亲和力 IL-2Rα 亚基组成型表达的 Tregs 来抑制免疫病理学。然而，即使是低剂量的 IL-2，通过 IL2-Rβ/γ 复合物信号传导，也可能导致促炎、非 Treg T 细胞的激活，因此提高对 Treg 的特异性可能是可取的。在这里，我们使用信使 RNA（mRNA）编码一种半衰期延长的人类 IL-2 突变体（HSA-IL2m），该突变体促进对 IL-2Rα 的依赖。我们的数据表明，脂质包裹的 mRNA 纳米颗粒作为皮下 IL-2 突变体传递选择性地激活和扩增小鼠和非人灵长类动物中的 Treg，还降低了急性移植物抗宿主病和实验性自身免疫性脑脊髓炎小鼠模型中的疾病严重程度。对小鼠脾脏 CD4 T 细胞的单细胞 RNA 测序鉴定了多种 Treg 状态，这些状态在接受 IL-2 突变体治疗后具有不同的反应动力学。因此，我们的结果表明，mRNA 编码的 HSA-IL2m 免疫疗法有可能治疗自身免疫性疾病。
