Zhu Feng, Willette-Brown Jami, Song Na-Young, Lomada Dakshayani, Song Yongmei, Xue Liyan, Gray Zane, Zhao Zitong, Davis Sean R, Sun Zhonghe, Zhang Peilin, Wu Xiaolin, Zhan Qimin, Richie Ellen R, Hu Yinling
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
Cell Host Microbe. 2017 Apr 12;21(4):478-493.e7. doi: 10.1016/j.chom.2017.03.006.
Humans with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a T cell-driven autoimmune disease caused by impaired central tolerance, are susceptible to chronic fungal infection and esophageal squamous cell carcinoma (ESCC). However, the relationship between autoreactive T cells and chronic fungal infection in ESCC development remains unclear. We find that kinase-dead Ikkα knockin mice develop APECED-like phenotypes, including impaired central tolerance, autoreactive T cells, chronic fungal infection, and ESCCs expressing specific human ESCC markers. Using this model, we investigated the link between ESCC and fungal infection. Autoreactive CD4 T cells permit fungal infection and incite tissue injury and inflammation. Antifungal treatment or autoreactive CD4 T cell depletion rescues, whereas oral fungal administration promotes, ESCC development. Inhibition of inflammation or epidermal growth factor receptor (EGFR) activity decreases fungal burden. Fungal infection is highly associated with ESCCs in non-autoimmune human patients. Therefore, autoreactive T cells and chronic fungal infection, fostered by inflammation and epithelial injury, promote ESCC development.
患有自身免疫性多内分泌腺病-念珠菌病-外胚层营养不良（APECED）的人，这是一种由中枢耐受受损引起的T细胞驱动的自身免疫性疾病，易患慢性真菌感染和食管鳞状细胞癌（ESCC）。然而，自身反应性T细胞与ESCC发生过程中慢性真菌感染之间的关系仍不清楚。我们发现，激酶失活的Ikkα基因敲入小鼠会出现类似APECED的表型，包括中枢耐受受损、自身反应性T细胞、慢性真菌感染以及表达特定人类ESCC标志物的ESCC。利用这个模型，我们研究了ESCC与真菌感染之间的联系。自身反应性CD4 T细胞会引发真菌感染，并导致组织损伤和炎症。抗真菌治疗或自身反应性CD4 T细胞耗竭可挽救ESCC的发展，而口服真菌则会促进ESCC的发展。抑制炎症或表皮生长因子受体（EGFR）活性可降低真菌负荷。在非自身免疫性人类患者中，真菌感染与ESCC高度相关。因此，由炎症和上皮损伤引发的自身反应性T细胞和慢性真菌感染会促进ESCC的发展。
