Centre for Immunology and Infection and York Biomedical Research Institute, Hull York Medical School and Department of Biology, University of York, York, UK.
Centre of Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, Charterhouse Square, Queen Mary University London, London, UK.
EMBO Rep. 2019 Apr;20(4). doi: 10.15252/embr.201846620. Epub 2019 Mar 4.
Determining the mechanisms that distinguish protective immunity from pathological chronic inflammation remains a fundamental challenge. miR-132 has been shown to play largely immunoregulatory roles in immunity; however, its role in CD4 T cell function is poorly understood. Here, we show that CD4 T cells express high levels of miR-132 and that T cell activation leads to miR-132 up-regulation. The transcriptomic hallmark of splenic CD4 T cells lacking the miR-132/212 cluster during chronic infection is an increase in mRNA levels of ribosomal protein (RP) genes. BTAF1, a co-factor of B-TFIID and novel miR-132/212-3p target, and p300 contribute towards miR-132/212-mediated regulation of RP transcription. Following infection with CD4 T cells display enhanced expression of IL-10 and decreased IFNγ. This is associated with reduced hepatosplenomegaly and enhanced pathogen load. The enhanced IL-10 expression in Th1 cells is recapitulated following treatment with phenylephrine, a drug reported to promote ribosome synthesis. Our results uncover that miR-132/212-mediated regulation of RP expression is critical for optimal CD4 T cell activation and protective immunity against pathogens.
确定区分保护性免疫与病理性慢性炎症的机制仍然是一个基本挑战。miR-132 在免疫中主要发挥免疫调节作用；然而，其在 CD4 T 细胞功能中的作用尚不清楚。在这里，我们表明 CD4 T 细胞表达高水平的 miR-132，并且 T 细胞激活导致 miR-132 的上调。慢性感染期间缺乏 miR-132/212 簇的脾 CD4 T 细胞的转录组特征是核糖体蛋白（RP）基因的 mRNA 水平增加。BTAF1 是 B-TFIID 的共因子和新型 miR-132/212-3p 靶标，以及 p300 有助于 miR-132/212 对 RP 转录的调节。感染后，CD4 T 细胞显示出增强的 IL-10 表达和减少的 IFNγ。这与肝脾肿大减少和病原体载量增加有关。在用苯肾上腺素（一种据报道可促进核糖体合成的药物）处理后，Th1 细胞中的增强的 IL-10 表达得到重现。我们的结果揭示了 miR-132/212 介导的 RP 表达调控对于最佳 CD4 T 细胞激活和针对病原体的保护性免疫至关重要。
