Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling
Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling
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DOI：
10.1038/leu.2011.179
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发表时间：
2012-01-01
期刊：
影响因子：
11.4
通讯作者：
Tarte, K.
中科院分区：
文献类型：
--
作者：
Epron, G.;Ame-Thomas, P.;Tarte, K.
白细胞介素-15 （IL-15）通过一种独特的产生细胞递呈机制在NK细胞和T细胞的存活和增殖中所起的作用已被广泛研究。相反，虽然活化的B细胞被描述为il -15应答细胞，但维持这种作用的细胞和分子背景仍未被探索。在这项研究中，我们发现，虽然人B细胞对可溶性IL-15没有反应，但单核细胞和淋巴组织来源的巨噬细胞却不能有效地将IL-15转化为正常B细胞，并与t细胞来源的CD40L合作，促进IL-15依赖性B细胞的增殖。此外，CD40L信号会触发src独立的STAT5表达上调，并在IL-15的作用下促进src依赖的STAT5磷酸化。在滤泡性淋巴瘤（FL）中，免疫组织化学研究报告了恶性B细胞、浸润性巨噬细胞和T细胞之间的密切关系。我们发现IL-15在纯化的肿瘤相关巨噬细胞中过表达，STAT5A在纯化的肿瘤B细胞中过表达。此外，FL B细胞对单核细胞/巨噬细胞反式呈递的IL-15有反应，特别是在cd40l介导的信号传导存在的情况下。IL-15和CD40L之间的这种合作强化了肿瘤微环境的重要性，揭示了IL-15作为药物治疗这种疾病时应考虑的FL生长机制。白血病（2012）26,139-148；doi: 10.1038 / leu.2011.179;2011年7月26日在线发布
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. Leukemia (2012) 26, 139-148; doi:10.1038/leu.2011.179; published online 26 July 2011