Kooy-Winkelaar Yvonne M C, Bouwer Dagmar, Janssen George M C, Thompson Allan, Brugman Martijn H, Schmitz Frederike, de Ru Arnoud H, van Gils Tom, Bouma Gerd, van Rood Jon J, van Veelen Peter A, Mearin M Luisa, Mulder Chris J, Koning Frits, van Bergen Jeroen
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.
Proc Natl Acad Sci U S A. 2017 Feb 7;114(6):E980-E989. doi: 10.1073/pnas.1620036114. Epub 2017 Jan 3.
Refractory celiac disease type II (RCDII) is a severe complication of celiac disease (CD) characterized by the presence of an enlarged clonal population of innate intraepithelial lymphocytes (IELs) lacking classical B-, T-, and natural killer (NK)-cell lineage markers (LinIELs) in the duodenum. In ∼50% of patients with RCDII, these LinIELs develop into a lymphoma for which no effective treatment is available. Current evidence indicates that the survival and expansion of these malignant LinIELs is driven by epithelial cell-derived IL-15. Like CD, RCDII is strongly associated with HLA-DQ2, suggesting the involvement of HLA-DQ2-restricted gluten-specific CD4 T cells. We now show that gluten-specific CD4 T cells isolated from CD duodenal biopsy specimens produce cytokines able to trigger proliferation of malignant LinIEL lines as powerfully as IL-15. Furthermore, we identify TNF, IL-2, and IL-21 as CD4 T-cell cytokines that synergistically mediate this effect. Like IL-15, these cytokines were found to increase the phosphorylation of STAT5 and Akt and transcription of antiapoptotic mediator bcl-x Several small-molecule inhibitors targeting the JAK/STAT pathway blocked proliferation elicited by IL-2 and IL-15, but only an inhibitor targeting the PI3K/Akt/mTOR pathway blocked proliferation induced by IL-15 as well as the CD4 T-cell cytokines. Confirming and extending these findings, TNF, IL-2, and IL-21 also synergistically triggered the proliferation of freshly isolated LinIELs and CD3CD56 IELs (NK-IELs) from RCDII as well as non-RCDII duodenal biopsy specimens. These data provide evidence implicating CD4 T-cell cytokines in the pathogenesis of RCDII. More broadly, they suggest that adaptive immune responses can contribute to innate IEL activation during mucosal inflammation.
II型难治性乳糜泻（RCDII）是乳糜泻（CD）的一种严重并发症，其特征是十二指肠中存在大量克隆性扩增的固有上皮内淋巴细胞（IEL），这些细胞缺乏经典的B细胞、T细胞和自然杀伤（NK）细胞谱系标志物（LinIELs）。在约50%的RCDII患者中，这些LinIELs会发展成淋巴瘤，目前尚无有效的治疗方法。现有证据表明，这些恶性LinIELs的存活和扩增是由上皮细胞衍生的IL-15驱动的。与CD一样，RCDII与HLA-DQ2密切相关，提示HLA-DQ2限制性谷蛋白特异性CD4 T细胞参与其中。我们现在发现，从CD十二指肠活检标本中分离出的谷蛋白特异性CD4 T细胞产生的细胞因子能够像IL-15一样强烈地触发恶性LinIEL系的增殖。此外，我们确定TNF、IL-2和IL-21是协同介导这种效应的CD4 T细胞细胞因子。与IL-15一样，这些细胞因子被发现可增加STAT5和Akt的磷酸化以及抗凋亡介质bcl-x的转录。几种靶向JAK/STAT途径的小分子抑制剂可阻断IL-2和IL-15诱导的增殖，但只有一种靶向PI3K/Akt/mTOR途径的抑制剂可阻断IL-15以及CD4 T细胞细胞因子诱导的增殖。TNF、IL-2和IL-21同样协同触发了从RCDII以及非RCDII十二指肠活检标本中新鲜分离的LinIELs和CD3CD56 IELs（NK-IELs）的增殖，从而证实并扩展了这些发现。这些数据提供了证据，表明CD4 T细胞细胞因子参与了RCDII的发病机制。更广泛地说，它们表明适应性免疫反应可在黏膜炎症期间促进固有IEL的激活。
