Qiu Huiying, Hu Xiaoxia, Gao Lei, Chen Li, Chen Jie, Yuan Joanna, Huang Chongmei, Xu Xiaoqian, Yang Jianmin
Department of Haematology, Institute of Haematology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
DICAT Biomedical Computation Centre, Vancouver, British Columbia, Canada.
Exp Cell Res. 2017 Nov 15;360(2):146-152. doi: 10.1016/j.yexcr.2017.08.036. Epub 2017 Sep 1.
The pleiotropic cytokine interleukin (IL)-10 is best characterized by its ability to downregulate inflammation and promote peripheral tolerance. On the other hand, IL-10 was also found to maintain the effector response of CD8 T cells and promote the expansion of tumor-resident CD8 T cells. In diffuse large B cell lymphoma (DLBCL), the role of IL-10 has been characterized in tumor cells but not in CD8 T cells. We found that CD8 T cells in DLBCL presented robust interferon (IFN)-γ expression early during TCR-activation but could not maintain this response later on, which was characterized by significantly lower CD8 T cell degranulation and higher apoptosis. These observations were associated with higher PD-1 expression in DLBCL CD8 T cells. Furthermore, the PD-1 cells were strongly enriched in the IFN-γ, but not the IFN-γ, fraction. Interestingly, exogenous IL-10 significantly improved the survival of DLBCL CD8 T cells, and resulted in significantly higher IFN-γ, ganzyme A and granzyme B expression in the absence of CD19 tumor cells, and significantly improved CD8 T cell-mediated specific lysis of CD19 tumor cells. IL-10 did not alter the expression of PD-1 in DLBCL CD8 T cells, but curiously, IL-10-treated DLBCL CD8 T cells were less susceptible to PD-L1-mediated apoptosis. We then demonstrated that IL-10 treatment significantly elevated the expression of pro-survival factor Bcl-2. Blocking IL-10 resulted in higher apoptosis, fewer IFN-γ CD8 T cells, and lower Bcl-2 expression. IL-10 also significantly increased STAT3, but not STAT1, phosphorylation in CD8 T cells. Together, these results suggested that IL-10 could enhance CD8 T cell inflammation in DLBCL patients.
多效细胞因子白细胞介素（IL）-10的最佳特征在于其下调炎症和促进外周耐受的能力。另一方面，还发现IL-10可维持CD8 T细胞的效应反应并促进肿瘤驻留CD8 T细胞的扩增。在弥漫性大B细胞淋巴瘤（DLBCL）中，IL-10在肿瘤细胞中的作用已得到明确，但在CD8 T细胞中的作用尚不明确。我们发现，DLBCL中的CD8 T细胞在TCR激活早期呈现出强烈的干扰素（IFN）-γ表达，但随后无法维持这种反应，其特征是CD8 T细胞脱颗粒显著减少且凋亡增加。这些观察结果与DLBCL CD8 T细胞中较高的PD-1表达相关。此外，PD-1细胞在IFN-γ而非IFN-γ组分中强烈富集。有趣的是，外源性IL-10显著提高了DLBCL CD8 T细胞的存活率，并在不存在CD19肿瘤细胞的情况下导致IFN-γ、颗粒酶A和颗粒酶B表达显著升高，且显著改善了CD8 T细胞介导的对CD19肿瘤细胞的特异性杀伤。IL-10并未改变DLBCL CD8 T细胞中PD-1的表达，但奇怪的是，经IL-10处理的DLBCL CD8 T细胞对PD-L1介导的凋亡更具抗性。然后我们证明，IL-10处理显著提高了促生存因子Bcl-2的表达。阻断IL-10会导致更高的凋亡率、更少的IFN-γ CD8 T细胞以及更低的Bcl-2表达。IL-10还显著增加了CD8 T细胞中STAT3而非STAT1的磷酸化。总之，这些结果表明IL-10可增强DLBCL患者CD8 T细胞的炎症反应。
