CD19loCD27hi Plasmablasts Suppress Harmful Th17 Inflammation Through Interleukin 10 Pathway in Colorectal Cancer
CD19loCD27hi Plasmablasts Suppress Harmful Th17 Inflammation Through Interleukin 10 Pathway in Colorectal Cancer
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DOI：
10.1089/dna.2017.3814
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发表时间：
2017-10-01
影响因子：
3.1
通讯作者：
Dai, Guanghai
中科院分区：
文献类型：
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作者：
Mao, Hui;Pan, Fei;Dai, Guanghai
CD 20（+）和CD 138（+）免疫细胞的富集与结直肠癌（CRC）生存率的提高有关。我们先前发现，CRC患者切除的肿瘤高度富集了具有潜在抑制功能的产生白细胞介素（IL）-10的CD 19（lo）CD 27（hi）浆母细胞。CD 19（lo）CD 27（hi）浆母细胞在结直肠癌患者中的作用尚不清楚。在这项研究中，我们首先证明，B细胞从外周血单核细胞（PBMC）可以刺激类似肿瘤浸润浆母细胞使用含有Caco-2和热灭活细菌的共培养物。PBMC来源的CD 19（lo）CD 27（hi）浆母细胞和肿瘤浸润浆母细胞含有相当频率的IL-10表达细胞，并分泌相似水平的IL-10。我们后来发现，这些CD 19（lo）CD 27（hi）浆母细胞显著抑制PBMC中IL-17 A的mRNA和细胞因子表达，以及CD 4（+）T细胞中RAR相关孤儿受体γ t（RORt）的表达。这种抑制作用不涉及Foxp 3（+）调节性T细胞的诱导，因为没有观察到Foxp 3水平的上调。通过IL-10/IL-10 R阻断和外源性IL-10实验，我们发现这些CD 19（lo）CD 27（hi）浆母细胞主要通过IL-10产生介导IL-17 A抑制。其他B细胞相关机制也可能有助于这种抑制作用。在我们的患者队列中，肿瘤浸润性IL-10（+）CD 19（lo）CD 27（hi）浆母细胞频率高的患者表现出较低的IL-17 A（+）CD 4（+）T细胞频率和较好的生存率。总之，这些结果表明，具有布雷格功能的CD 19（lo）CD 27（hi）浆母细胞与CRC的较好预后相关，可能是通过抑制有害的Th 17炎症。
The enrichment of CD20(+) and CD138(+) immune cells were previously associated with improved survival in colorectal cancer (CRC). We previously discovered that the resected tumors in CRC patients were highly enriched with interleukin (IL)-10-producing CD19(lo)CD27(hi) plasmablasts with potential suppressor functions. It is still unknown what roles the CD19(lo)CD27(hi) plasmablasts play in CRC patients. In this study, we first demonstrated that B cells from peripheral blood mononuclear cells (PBMCs) could be stimulated to resemble tumor-infiltrating plasmablasts using a coculture containing Caco-2 and heat-killed bacteria. The PBMC-derived CD19(lo)CD27(hi) plasmablasts and tumor-infiltrating plasmablasts contained comparable frequencies of IL-10-expressing cells and secreted similar levels of IL-10. We later found that these CD19(lo)CD27(hi) plasmablasts significantly suppressed the mRNA and cytokine expression of IL-17A in PBMCs, as well as the expression of RAR-related orphan receptor gamma t (RORt) in CD4(+) T cells. This suppressive effect did not involve the induction of Foxp3(+) regulatory T cells, since no upregulation of Foxp3 level was observed. Through IL-10/IL-10R blocking and exogenous IL-10 experiments, we found that these CD19(lo)CD27(hi) plasmablasts primarily mediated IL-17A suppression through IL-10 production. Other B cell-related mechanisms might also contribute to this inhibitory effect. In our cohort of patients, patients with high frequency of tumor-infiltrating IL-10(+) CD19(lo)CD27(hi) plasmablasts presented low IL-17A(+) CD4(+) T cell frequency and better survival. Altogether, these results suggested that CD19(lo)CD27(hi) plasmablasts with Breg functions were associated with better prognosis in CRC, possibly by suppressing harmful Th17 inflammation.