Autoreactive T Cells and Chronic Fungal Infection Drive Esophageal Carcinogenesis

Publication date: 12 April 2017
Source:Cell Host & Microbe, Volume 21, Issue 4
Author(s): Feng Zhu, Jami Willette-Brown, Na-Young Song, Dakshayani Lomada, Yongmei Song, Liyan Xue, Zane Gray, Zitong Zhao, Sean R. Davis, Zhonghe Sun, Peilin Zhang, Xiaolin Wu, Qimin Zhan, Ellen R. Richie, Yinling Hu
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.

Graphical abstract

Teaser

The role of fungal infection in carcinogenesis remains unknown. Zhu et al. demonstrate that autoreactive CD4 T cells permit fungal infection and incite inflammation. Inflammation and EGFR activity facilitate chronic fungal infection in the epithelium. Fungal infection promotes ESCC development. The findings highlight therapeutic avenues for HESCC prevention and treatment.


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