CD4+ T cells sustain aggressive chronic lymphocytic leukemia in Eμ-TCL1 mice through a CD40L-independent mechanism
CD4+ T cells sustain aggressive chronic lymphocytic leukemia in Eμ-TCL1 mice through a CD40L-independent mechanism
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DOI：
10.1182/bloodadvances.2020003795
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发表时间：
2021-07-17
期刊：
影响因子：
7.5
通讯作者：
Calcinotto, Arianna
中科院分区：
文献类型：
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作者：
Grioni, Matteo;Brevi, Arianna;Calcinotto, Arianna
慢性淋巴细胞白血病（CLL）是由成熟的CD5(+) B细胞在次级淋巴器官的进行性积累引起的。体外数据表明，CD4(+) T淋巴细胞也通过CD40L/CD40相互作用维持CLL克隆的生存和增殖。动物模型的体内数据是相互矛盾的。为了澄清这一临床相关的生物学问题，我们培养了缺乏CD4(+) T细胞（TCL1(+/+)AB0）、CD40(TCL1(+/+)CD40（-/-）或CD8(+) T细胞(TCL1（+/+)TAP(-/-)）的转基因E mu-TCL1小鼠，并通过流式细胞术和免疫组织化学分析监测了一种模仿侵袭性人类CLL的疾病的出现和进展。通过将白血病细胞过继转移到缺乏CD4(+) T细胞或CD40L的小鼠或用抗体消耗CD4 T细胞或阻断CD40L/CD40相互作用的小鼠中，证实了这一发现。CLL克隆在缺乏或缺乏CD4(+) T细胞的小鼠中不增殖，从而证实CD4(+) T细胞对CLL的发展至关重要。相比之下，CD8(+) T细胞发挥抗肿瘤活性，正如TCL1(+/+)TAP（-/-）小鼠的疾病加速进展所表明的那样。CD4(+) T细胞的抗原特异性对于CLL的发展是边缘性的，因为CLL克隆在CD4 T细胞具有与CLL无关特异性的T细胞受体的转基因小鼠中有效增殖。当将白血病克隆转移到用阻断CD40的单克隆抗体处理的野生型小鼠或CD40L（-/-）小鼠体内时，白血病克隆也会增殖，而TCL1(+/+)CD40（-/-）小鼠则发展为纯CLL。我们的数据表明，CD8(+) T细胞抑制CLL的进展，而CD4(+) T细胞通过cd40独立和明显非同源的机制支持TCL1小鼠白血病克隆的生长。
Chronic lymphocytic leukemia (CLL) is caused by the progressive accumulation of mature CD5(+) B cells in secondary lymphoid organs. In vitro data suggest that CD4(+) T lymphocytes also sustain survival and proliferation of CLL clones through CD40L/CD40 interactions. In vivo data in animal models are conflicting. To clarify this clinically relevant biological issue, we generated genetically modified E mu-TCL1 mice lacking CD4(+) T cells (TCL1(+/+)AB0), CD40 (TCL1(+/+)CD40(-/-)), or CD8(+) T cells (TCL1(+/+)TAP(-/-)), and we monitored the appearance and progression of a disease that mimics aggressive human CLL by flow cytometry and immunohistochemical analyses. Findings were confirmed by adoptive transfer of leukemic cells into mice lacking CD4(+) T cells or CD40L or mice treated with antibodies depleting CD4 T cells or blocking CD40L/CD40 interactions. CLL clones did not proliferate in mice lacking or depleted of CD4(+) T cells, thus confirming that CD4(+) T cells are essential for CLL development. By contrast, CD8(+) T cells exerted an antitumor activity, as indicated by the accelerated disease progression in TCL1(+/+)TAP(-/-) mice. Antigen specificity of CD4(+) T cells was marginal for CLL development, because CLL clones efficiently proliferated in transgenic mice whose CD4 T cells had a T-cell receptor with CLL-unrelated specificities. Leukemic clones also proliferated when transferred into wild-type mice treated with monoclonal antibodies blocking CD40 or into CD40L(-/-) mice, and TCL1(+/+)CD40(-/-) mice developed frank CLL. Our data demonstrate that CD8(+) T cells restrain CLL progression, whereas CD4(+) T cells support the growth of leukemic clones in TCL1 mice through CD40-independent and apparently noncognate mechanisms.