Systemic administration of IL-33 induces a population of circulating KLRG1hi type 2 innate lymphoid cells and inhibits type 1 innate immunity against multiple myeloma.,Immunology and Cell Biology

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Systemic administration of IL-33 induces a population of circulating KLRG1hi type 2 innate lymphoid cells and inhibits type 1 innate immunity against multiple myeloma.
Immunology and Cell Biology ( IF 3.2 ) Pub Date : 2020-08-04 , DOI: 10.1111/imcb.12390
Camille Guillerey _{1,

2} , Kimberley Stannard ₁ , Jason Chen _{1,

2} , Sophie Krumeich ₁ , Kim Miles ₁ , Kyohei Nakamura ₁ , Jessica Smith _{1,

3} , Yuan Yu ₁ , Susanna Ng ₄ , Heidi Harjunpää _{2,

5} , Michele Wl Teng ₅ , Christian Engwerda ₄ , Gabrielle T Belz ₆ , Mark J Smyth _{1,

2}

Affiliation

Type 2 innate lymphoid cells (ILC2s) are important producers of type 2 cytokines whose role in hematological cancers remains unclear. ILC2s are a heterogeneous population encompassing distinct subsets with different tissue localization and cytokine responsiveness. In this study, we investigated the role of bone marrow (BM) ILC2s and interleukin (IL)‐33‐stimulated ILC2s in multiple myeloma, a plasma cell malignancy that develops in the BM. We found that myeloma growth was associated with phenotypic and functional alterations of BM ILC2s, characterized by an increased expression of maturation markers and reduced cytokine response to IL‐2/IL‐33. We identified a population of KLRG1^hi ILC2s that preferentially accumulated in the liver and spleen of Il2rg^−/− Rag2^−/− mice reconstituted with BM ILC2s. A similar population of KLRG1^hi ILC2s was observed in the blood, liver and spleen of IL‐33‐treated wild‐type mice. The presence of KLRG1^hi ILC2s in ILC2‐reconstituted Il2rg^−/− Rag2^−/− mice or in IL‐33‐treated wild‐type mice was associated with increased eosinophil numbers but had no effect on myeloma progression. Interestingly, while decreased myeloma growth was observed following treatment of Rag‐deficient mice with the type 1 cytokines IL‐12 and IL‐18, this protection was reversed when mice received a combined treatment of IL‐33 together with IL‐12 and IL‐18. In summary, our data indicate that IL‐33 treatment induces a population of circulating inflammatory KLRG1^hi ILC2s and inhibits type 1 immunity against multiple myeloma. These results argue against therapeutic administration of IL‐33 to myeloma patients.

中文翻译：

IL-33 的全身给药诱导循环 KLRG1hi 2 型先天淋巴细胞群并抑制针对多发性骨髓瘤的 1 型先天免疫。

2 型先天淋巴细胞 (ILC2) 是 2 型细胞因子的重要生产者，其在血液癌症中的作用尚不清楚。ILC2s 是一个异质群体，包括具有不同组织定位和细胞因子反应性的不同亚群。在这项研究中，我们研究了骨髓 (BM) ILC2s 和白细胞介素 (IL)-33 刺激的 ILC2s 在多发性骨髓瘤中的作用，多发性骨髓瘤是一种在 BM 中发展的浆细胞恶性肿瘤。我们发现骨髓瘤的生长与 BM ILC2s 的表型和功能改变有关，其特征是成熟标志物的表达增加和对 IL-2/IL-33 的细胞因子反应降低。我们鉴定了一群KLRG1 ^hi ILC2s，它们优先积聚在Il2rg ^-/- Rag2 ^-/-的肝脏和脾脏中用 BM ILC2s 重组的小鼠。在 IL-33 处理的野生型小鼠的血液、肝脏和脾脏中观察到类似的 KLRG1 ^hi ILC2群体。在 ILC2 重建的Il2rg ^-/-Rag2 ^-/-小鼠或 IL-33 处理的野生型小鼠中，KLRG1 ^hi ILC2s的存在与嗜酸性粒细胞数量增加有关，但对骨髓瘤进展没有影响。有趣的是，虽然在用 1 型细胞因子 IL-12 和 IL-18 治疗 Rag 缺陷小鼠后观察到骨髓瘤生长减少，但当小鼠接受 IL-33 与 IL-12 和 IL- 联合治疗时，这种保护作用被逆转18. 总之，我们的数据表明 IL-33 治疗诱导了一群循环炎症 KLRG1 ^hi ILC2s 并抑制针对多发性骨髓瘤的 1 型免疫。这些结果反对将 IL-33 用于骨髓瘤患者的治疗性给药。

更新日期：2020-08-04

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