Tosiek Milena J, Fiette Laurence, El Daker Sary, Eberl Gérard, Freitas Antonio A
Unité de Biologie des Populations Lymphocytaires, Department of Immunology, Institut Pasteur, 25, rue du Docteur Roux, 75015 Paris, France.
CNRS, URA1961, 75015 Paris, France.
Nat Commun. 2016 Mar 11;7:10888. doi: 10.1038/ncomms10888.
The ability of CD4+ T cells to change their phenotype and to specialize into different functional subsets may enhance the risk of autoimmune diseases. Here we investigate how a pleiotropic cytokine interleukin (IL)-15 may modify the functional commitment of CD4+ T cells expressing the lineage-associated transcription factors: forkhead box P3 (Foxp3; Treg) and RORγt (Th17) in the context of inflammatory bowel disease (IBD). We demonstrate in mice that impaired delivery of IL-15 to CD4+ T cells in the colon downmodulates Foxp3 expression (diminishing STAT5 phosphorylation) and enhances RORγt expression (by upregulating the expression of Runx1). In consequence, CD4+ T cells deprived of IL-15 rapidly trigger IBD characterized by enhanced production of pro-inflammatory cytokines (interferon-γ, IL-6) and accumulation of Th1/Th17 cells. Overall, our findings indicate a potentially beneficial role of IL-15 in IBD by fine-tuning the balance between Treg and Th17 cells and controlling intestinal inflammation.
CD4+ T细胞改变其表型并分化为不同功能亚群的能力可能会增加自身免疫性疾病的风险。在此，我们研究了多效性细胞因子白细胞介素（IL）-15在炎症性肠病（IBD）背景下如何改变表达谱系相关转录因子叉头框P3（Foxp3；调节性T细胞）和维甲酸相关孤儿受体γt（RORγt；辅助性T细胞17）的CD4+ T细胞的功能定向。我们在小鼠中证明，结肠中IL-15向CD4+ T细胞的递送受损会下调Foxp3表达（减少信号转导和转录激活因子5磷酸化）并增强RORγt表达（通过上调Runx1的表达）。因此，缺乏IL-15的CD4+ T细胞会迅速引发以促炎细胞因子（干扰素-γ、IL-6）产生增加和辅助性T细胞1/辅助性T细胞17细胞积聚为特征的IBD。总体而言，我们的研究结果表明IL-15通过微调调节性T细胞和辅助性T细胞17细胞之间的平衡并控制肠道炎症，在IBD中可能发挥有益作用。
