Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy.
Department of Oncology and Hemato-oncology, Università degli Studi di Milano, Milan, Italy.
J Crohns Colitis. 2022 Sep 8;16(9):1461-1474. doi: 10.1093/ecco-jcc/jjac049.
Invariant natural killer T [iNKT] cells perform pleiotropic functions in different tissues by secreting a vast array of pro-inflammatory and cytotoxic molecules. However, the presence and function of human intestinal iNKT cells capable of secreting immunomodulatory molecules such as IL-10 has never been reported so far. Here we describe for the first time the presence of IL10-producing iNKT cells [NKT10 cells] in the intestinal lamina propria of healthy individuals and of Crohn's disease [CD] patients.
Frequency and phenotype of NKT10 cells were analysed ex vivo from intestinal specimens of Crohn's disease [n = 17] and controls [n = 7]. Stable CD-derived intestinal NKT10 cell lines were used to perform in vitro suppression assays and co-cultures with patient-derived mucosa-associated microbiota. Experimental colitis models were performed by adoptive cell transfer of splenic naïve CD4+ T cells in the presence or absence of IL10-sufficient or -deficient iNKT cells. In vivo induction of NKT10 cells was performed by administration of short chain fatty acids [SCFA] by oral gavage.
Patient-derived intestinal NKT10 cells demonstrated suppressive capabilities towards pathogenic CD4+ T cells. The presence of increased proportions of mucosal NKT10 cells associated with better clinical outcomes in CD patients. Moreover, an intestinal microbial community enriched in SCFA-producing bacteria sustained the production of IL10 by iNKT cells. Finally, IL10-deficient iNKT cells failed to control the pathogenic activity of adoptively transferred CD4+ T cells in an experimental colitis model.
These results describe an unprecedentd IL10-mediated immunoregulatory role of intestinal iNKT cells in controlling the pathogenic functions of mucosal T helper subsets and in maintaining the intestinal immune homeostasis.
不变自然杀伤 T [iNKT] 细胞通过分泌大量促炎和细胞毒性分子在不同组织中发挥多种功能。然而，具有分泌免疫调节分子如 IL-10 能力的人类肠道 iNKT 细胞的存在和功能迄今为止尚未报道。在这里，我们首次描述了健康个体和克罗恩病 [CD] 患者肠道固有层中存在产生 IL-10 的 iNKT 细胞 [NKT10 细胞]。
分析了来自 CD [n = 17]和对照 [n = 7]肠道标本的 NKT10 细胞的频率和表型。使用稳定的 CD 衍生的肠道 NKT10 细胞系进行体外抑制试验和与患者来源的粘膜相关微生物群的共培养。通过在存在或不存在 IL-10 充足或缺乏的 iNKT 细胞的情况下，将脾脏幼稚 CD4+ T 细胞过继转移到实验性结肠炎模型中，进行体内 NKT10 细胞诱导。
患者衍生的肠道 NKT10 细胞对致病性 CD4+ T 细胞具有抑制作用。与 CD 患者更好的临床结果相关的粘膜 NKT10 细胞比例增加。此外，富含产生 SCFA 细菌的肠道微生物群落维持了 iNKT 细胞产生 IL-10。最后，IL-10 缺陷型 iNKT 细胞未能控制实验性结肠炎模型中过继转移的 CD4+ T 细胞的致病性活性。
这些结果描述了肠道 iNKT 细胞在控制粘膜辅助性 T 细胞亚群的致病性功能和维持肠道免疫稳态方面的前所未有的 IL-10 介导的免疫调节作用。
