Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
J Crohns Colitis. 2018 Jul 30;12(8):981-992. doi: 10.1093/ecco-jcc/jjy051.
T helper 17 [Th17] cells are crucially involved in the immunopathogenesis of inflammatory bowel diseases in humans. Nevertheless, pharmacological blockade of interleukin 17A [IL17A], the Th17 signature cytokine, yielded negative results in patients with Crohn's disease [CD], and attempts to elucidate the determinants of Th17 cells' pathogenicity in the gut have so far proved unsuccessful. Here, we aimed to identify and functionally validate the pathogenic determinants of intestinal IL-17-producing T cells.
In vivo-generated murine intestinal IL-17-producing T cells were adoptively transferred into immunodeficient Rag1-/- recipients to test their pathogenicity. Human IL-17, IFNγ/IL-17, and IFNγ actively secreting T cell clones were generated from lamina propria lymphocytes of CD patients. The pathogenic activity of intestinal IL-17-producing T cells against the intestinal epithelium was evaluated.
IL-17-producing cells with variable colitogenic activity can be generated in vivo using different experimental colitis models. The pathogenicity of IL-17-secreting cells was directly dependent on their IFNγ secretion capacity, as demonstrated by the reduced colitogenic activity of IL-17-secreting cells isolated from IFNγ-/- mice. Moreover, IFNγ production is a distinguished attribute of CD-derived lamina propria Th17 cells. IFNγ secretion by CD-derived IL-17-producing intestinal clones is directly implicated in the epithelial barrier disruption through the modulation of tight junction proteins.
Intestinal Th17 cell pathogenicity is associated with IFNγ production, which directly affects intestinal permeability through the disruption of epithelial tight junctions.
辅助性 T 细胞 17（Th17）细胞在人类炎症性肠病的免疫发病机制中起着至关重要的作用。然而，白介素 17A（IL17A），Th17 特征细胞因子的药物阻断在克罗恩病[CD]患者中并未产生阳性结果，并且迄今为止，阐明 Th17 细胞在肠道中的致病性决定因素的尝试均未成功。在此，我们旨在鉴定并功能验证肠道产生白介素-17 的 T 细胞的致病性决定因素。
将体内生成的鼠肠道产生 IL-17 的 T 细胞过继转移到免疫缺陷 Rag1-/-受体内，以测试其致病性。从 CD 患者的固有层淋巴细胞中生成人 IL-17、IFNγ/IL-17 和 IFNγ 主动分泌的 T 细胞克隆。评估肠道产生 IL-17 的 T 细胞对肠道上皮的致病性。
使用不同的实验性结肠炎模型，可在体内产生具有不同结肠炎发病活性的 IL-17 产生细胞。IL-17 分泌细胞的致病性直接取决于其 IFNγ 分泌能力，这可通过从 IFNγ-/- 小鼠中分离出的 IL-17 分泌细胞的结肠炎发病活性降低来证明。此外，IFNγ 产生是 CD 来源固有层 Th17 细胞的一个显著特征。CD 来源产生 IL-17 的肠道克隆的 IFNγ 分泌直接通过调节紧密连接蛋白而导致上皮屏障破坏，从而参与上皮屏障破坏。
肠道 Th17 细胞的致病性与 IFNγ 产生有关，其通过破坏上皮紧密连接直接影响肠道通透性。
