Murine cytotoxic CD4+ T cells in the tumor microenvironment are at a hyper-maturation stage of Th1 CD4+ T cells sustained by IL-12.

IF 4.8 4区 医学 Q2 IMMUNOLOGY
Yung-Chang Lin, Cheng-Heng Wu, Pin-Jung Chen, Chien-Hao Huang, Chan-Keng Yang, Avijit Dutta, Ching-Tai Huang, Chun-Yen Lin
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Abstract

The roles of tumor-infiltrating CD4+Foxp3- T cells are not well characterized due to their plasticity of differentiation, and varying levels of activation or exhaustion. To further clarify this issue, we used a model featuring subcutaneous murine colon cancer and analyzed the dynamic changes of phenotype and function of the tumor-associated CD4+ T-cell response. We found that, even at a late stage of tumor growth, the tumor-infiltrating CD4+Foxp3- T cells still expressed effector molecules, inflammatory cytokines and molecules that are expressed at reduced levels in exhausted cells. We used microarrays to examine the gene-expression profiles of different subsets of CD4+ T cells and revealed that the tumor-infiltrating CD4+Foxp3- T cells expressed not only type 1 helper (Th1) cytokines, but also cytolytic granules such as those encoded by Gzmb and Prf1. In contrast to CD4+ regulatory T cells, these cells exclusively co-expressed natural killer receptor markers and cytolytic molecules as shown by flow-cytometry studies. We used an ex vivo killing assay and proved that they could directly suppress CT26 tumor cells through granzyme B and perforin. Finally, we used pathway analysis and ex vivo stimulation to confirm that the CD4+Foxp3- T cells expressed higher levels of IL12rb1 genes and were activated by the IL-12/IL-27 pathway. In conclusion, this work finds that, in late-stage tumors, the tumor-infiltrating lymphocyte population of CD4+ cells harbored a sustained, hyper-maturated Th1 status with cytotoxic function supported by IL-12.

肿瘤微环境中的小鼠细胞毒性CD4+ T细胞在IL-12的支持下处于Th1 CD4+ T细胞的超成熟阶段。
由于肿瘤浸润性CD4+Foxp3- T细胞的分化可塑性和不同程度的激活或衰竭,其作用尚未得到很好的表征。为了进一步澄清这一问题,我们采用小鼠皮下结肠癌模型,分析了肿瘤相关CD4+ t细胞反应的表型和功能的动态变化。我们发现,即使在肿瘤生长的后期,浸润肿瘤的CD4+Foxp3- T细胞仍然表达效应分子、炎症细胞因子和在衰竭细胞中表达水平降低的分子。我们利用微阵列技术检测了CD4+ T细胞不同亚群的基因表达谱,发现浸润肿瘤的CD4+Foxp3- T细胞不仅表达1型辅助细胞因子(Th1),还表达由Gzmb和Prf1编码的细胞溶解颗粒。流式细胞术研究显示,与CD4+调节性T细胞相比,这些细胞完全共表达自然杀伤受体标记物和细胞溶解分子。我们用离体杀伤实验证明它们可以通过颗粒酶B和穿孔素直接抑制CT26肿瘤细胞。最后,我们通过通路分析和离体刺激证实了CD4+Foxp3- T细胞表达更高水平的IL12rb1基因,并通过IL-12/IL-27途径被激活。总之,本研究发现,在晚期肿瘤中,浸润肿瘤的CD4+淋巴细胞群具有持续的、高度成熟的Th1状态,并具有IL-12支持的细胞毒性功能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International immunology
International immunology 医学-免疫学
CiteScore
9.30
自引率
2.30%
发文量
51
审稿时长
6-12 weeks
期刊介绍: International Immunology is an online only (from Jan 2018) journal that publishes basic research and clinical studies from all areas of immunology and includes research conducted in laboratories throughout the world.
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