INSERM U917, Université Rennes 1, Institut Fédératif de Recherche 140 Génomique Fonctionnelle Agronomie Santé, Rennes, France.
Leukemia. 2012 Jan;26(1):139-48. doi: 10.1038/leu.2011.179. Epub 2011 Jul 26.
Interleukin-15 (IL-15) has been extensively studied for its role in the survival and proliferation of NK and T cells through a unique mechanism of trans-presentation by producer cells. Conversely, whereas activated B cells have been described as IL-15-responding cells, the cellular and molecular context sustaining this effect remains unexplored. In this study, we found that, whereas human B cells could not respond to soluble IL-15, monocytes and lymphoid tissue-derived macrophages but not stromal cells efficiently trans-present IL-15 to normal B cells and cooperate with T-cell-derived CD40L to promote IL-15-dependent B-cell proliferation. Furthermore, CD40L signaling triggers a Src-independent upregulation of STAT5 expression and favors a Src-dependent phosphorylation of STAT5 in response to IL-15. In follicular lymphoma (FL), immunohistochemical studies reported a strong relationship between malignant B cells, infiltrating macrophages and T cells. We show here an overexpression of IL-15 in purified tumor-associated macrophages, and STAT5A in purified tumor B cells. Moreover, FL B cells respond to IL-15 trans-presented by monocytes/macrophages, in particular, in the presence of CD40L-mediated signaling. This cooperation between IL-15 and CD40L reinforces the importance of tumor microenvironment and unravels a mechanism of FL growth that should be considered if using IL-15 as a drug in this disease.
白细胞介素-15（IL-15）通过生产者细胞的转呈作用这一独特机制，广泛研究其在 NK 和 T 细胞存活和增殖中的作用。相反，虽然已描述激活的 B 细胞为 IL-15 反应细胞，但支持这种效应的细胞和分子背景仍未得到探索。在这项研究中，我们发现，虽然人 B 细胞不能对可溶性 IL-15 作出反应，但单核细胞和淋巴组织来源的巨噬细胞，但不是基质细胞，能够有效地将 IL-15 转呈给正常 B 细胞，并与 T 细胞衍生的 CD40L 合作，促进 IL-15 依赖性 B 细胞增殖。此外，CD40L 信号触发 STAT5 表达的Src 非依赖性上调，并有利于 Src 依赖性 STAT5 磷酸化，以响应 IL-15。在滤泡性淋巴瘤（FL）中，免疫组织化学研究报告称，恶性 B 细胞、浸润的巨噬细胞和 T 细胞之间存在很强的关系。我们在这里显示，纯化的肿瘤相关巨噬细胞中 IL-15 的表达过度，纯化的肿瘤 B 细胞中 STAT5A 的表达过度。此外，FL B 细胞对单核细胞/巨噬细胞转呈的 IL-15 作出反应，特别是在 CD40L 介导的信号存在下。IL-15 和 CD40L 之间的这种合作加强了肿瘤微环境的重要性，并揭示了 FL 生长的一种机制，如果在这种疾病中使用 IL-15 作为药物，应考虑这种机制。
