Table_1_Mobilized Multipotent Hematopoietic Progenitors Stabilize and Expand Regulatory T Cells to Protect Against Autoimmune Encephalomyelitis.xlsx

Achieving immunoregulation via in vivo expansion of Foxp3+ regulatory CD4+ T cells (Treg) remains challenging. We have shown that mobilization confers to multipotent hematopoietic progenitors (MPPs) the capacity to enhance Treg proliferation. Transcriptomic analysis of Tregs co-cultured with MPPs revealed enhanced expression of genes stabilizing the suppressive function of Tregs as well as the activation of IL-1β–driven pathways. Adoptive transfer of only 25,000 MPPs effectively reduced the development of experimental autoimmune encephalomyelitis (EAE), a pre-clinical model for multiple sclerosis (MS). Production of the pathogenic cytokines IL-17 and GM-CSF by spinal cord-derived CD4+ T-cells in MPP-protected recipients was reduced while Treg expansion was enhanced. Treg depletion once protection by MPPs was established, triggered disease relapse to the same level as in EAE mice without MPP injection. The key role of IL-1β was further confirmed in vivo by the lack of protection against EAE in recipients of IL-1β–deficient MPPs. Mobilized MPPs may thus be worth considering for cell therapy of MS either per se or for enrichment of HSC grafts in autologous bone marrow transplantation already implemented in patients with severe refractory multiple sclerosis.

通过体内扩增叉头框P3+调节性CD4+T细胞（Foxp3+ regulatory CD4+ T cells, Treg）实现免疫调节仍极具挑战。我们的研究证实，对多能造血祖细胞（multipotent hematopoietic progenitors, MPPs）进行动员，可使其获得增强Treg增殖的能力。对与MPPs共培养的Treg开展转录组分析后发现，稳定Treg免疫抑制功能的相关基因表达显著上调，同时白细胞介素-1β（IL-1β）介导的信号通路被激活。仅通过过继输注25000个MPPs，即可有效延缓实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis, EAE）的病情进展——该模型是多发性硬化（multiple sclerosis, MS）的经典临床前研究模型。在接受MPPs治疗的受体小鼠体内，脊髓来源CD4+T细胞分泌的致病性细胞因子白细胞介素-17（IL-17）与粒细胞-巨噬细胞集落刺激因子（GM-CSF）水平显著降低，同时Treg的扩增效果得到增强。一旦MPPs建立的免疫保护效应被消除，耗竭Treg会导致疾病复发至未输注MPPs的EAE小鼠的疾病严重程度。进一步的体内实验验证了IL-1β的关键作用：携带IL-1β基因缺陷的MPPs无法为受体小鼠提供针对EAE的免疫保护。因此，动员后的MPPs有望应用于MS的细胞治疗，既可单独用于临床治疗，也可用于强化难治性多发性硬化患者自体骨髓移植中的造血干细胞（Hematopoietic Stem Cell, HSC）移植物富集——该疗法目前已在难治性多发性硬化患者中开展。