Induction of stable human FOXP3+ Tregs by a parasite-derived TGF-β mimic,Immunology and Cell Biology

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Induction of stable human FOXP3+ Tregs by a parasite-derived TGF-β mimic
Immunology and Cell Biology ( IF 3.2 ) Pub Date : 2021-04-30 , DOI: 10.1111/imcb.12475
Laura Cook _{1,

2} , Kyle T Reid ₂ , Elmeri Häkkinen ₂ , Brett Bie ₂ , Shigeru Tanaka ₃ , Danielle J Smyth ₄ , Madeleine PJ White ₄ , May Q Wong _{1,

2} , Qing Huang _{2,

5} , Jana K Gillies _{2,

5} , Steven F. Ziegler ₃ , Rick M Maizels ₄ , Megan K Levings _{2,

5,

6}

Affiliation

Immune homeostasis in the intestine is tightly controlled by FOXP3⁺ regulatory T cells (Tregs), defects of which are linked to the development of chronic conditions, such as inflammatory bowel disease (IBD). As a mechanism of immune evasion, several species of intestinal parasites boost Treg activity. The parasite Heligmosomoides polygyrus is known to secrete a molecule (Hp-TGM) that mimics the ability of TGF-β to induce FOXP3 expression in CD4⁺ T cells. The study aimed to investigate whether Hp-TGM could induce human FOXP3⁺ Tregs as a potential therapeutic approach for inflammatory diseases. CD4⁺ T cells from healthy volunteers were expanded in the presence of Hp-TGM or TGF-β. Treg induction was measured by flow cytometric detection of FOXP3 and other Treg markers, such as CD25 and CTLA-4. Epigenetic changes were detected using ChIP-Seq and pyrosequencing of FOXP3. Treg phenotype stability was assessed following inflammatory cytokine challenge and Treg function was evaluated by cellular co-culture suppression assays and cytometric bead arrays for secreted cytokines. Hp-TGM efficiently induced FOXP3 expression (> 60%), in addition to CD25 and CTLA-4, and caused epigenetic modification of the FOXP3 locus to a greater extent than TGF-β. Hp-TGM-induced Tregs had superior suppressive function compared with TGF-β-induced Tregs, and retained their phenotype following exposure to inflammatory cytokines. Furthermore, Hp-TGM induced a Treg-like phenotype in in vivo differentiated Th1 and Th17 cells, indicating its potential to re-program memory cells to enhance immune tolerance. These data indicate Hp-TGM has potential to be used to generate stable human FOXP3⁺ Tregs to treat IBD and other inflammatory diseases.

中文翻译：

通过寄生虫衍生的 TGF-β 模拟物诱导稳定的人 FOXP3+ Tregs

肠道中的免疫稳态由 FOXP3 ⁺调节性 T 细胞 (Tregs)严格控制，其缺陷与慢性疾病的发展有关，例如炎症性肠病 (IBD)。作为免疫逃避的一种机制，几种肠道寄生虫会促进 Treg 活性。已知寄生虫Heligmosomoides polygyrus会分泌一种分子 ( Hp- TGM)，该分子模拟 TGF-β 在 CD4 ⁺ T 细胞中诱导 FOXP3 表达的能力。该研究旨在调查Hp- TGM是否可以诱导人类 FOXP3 ⁺ Tregs 作为炎症性疾病的潜在治疗方法。CD4 ⁺来自健康志愿者的 T 细胞在Hp -TGM 或 TGF-β存在下扩增。通过流式细胞术检测 FOXP3 和其他 Treg 标记物（如 CD25 和 CTLA-4）来测量 Treg 诱导。使用 ChIP-Seq 和FOXP3焦磷酸测序检测表观遗传变化。在炎症细胞因子攻击后评估 Treg 表型稳定性，并通过细胞共培养抑制测定和细胞计数珠阵列评估分泌细胞因子的 Treg 功能。除了 CD25 和 CTLA-4 外，Hp- TGM 还有效诱导 FOXP3 表达（> 60%），并且比 TGF-β 在更大程度上引起FOXP3基因座的表观遗传修饰。生命值-与 TGF-β 诱导的 Tregs 相比，TGM 诱导的 Tregs 具有更好的抑制功能，并且在暴露于炎性细胞因子后保留了它们的表型。此外，Hp -TGM在体内分化的 Th1 和 Th17 细胞中诱导 Treg 样表型，表明其重新编程记忆细胞以增强免疫耐受性的潜力。这些数据表明Hp- TGM 有可能用于产生稳定的人类 FOXP3 ⁺ Tregs 以治疗 IBD 和其他炎症性疾病。

更新日期：2021-04-30

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