TY - JOUR
T1 - Autoreactive T Cells and Chronic Fungal Infection Drive Esophageal Carcinogenesis
AU - Zhu, Feng
AU - Willette-Brown, Jami
AU - Song, Na Young
AU - Lomada, Dakshayani
AU - Song, Yongmei
AU - Xue, Liyan
AU - Gray, Zane
AU - Zhao, Zitong
AU - Davis, Sean R.
AU - Sun, Zhonghe
AU - Zhang, Peilin
AU - Wu, Xiaolin
AU - Zhan, Qimin
AU - Richie, Ellen R.
AU - Hu, Yinling
N1 - Funding Information:
This work was supported by funding from the National Cancer Institute, NIH (CA-102510, ZIA BC011212, and ZIA BC 011391) to Y.H.
Publisher Copyright:
© 2017
PY - 2017/4/12
Y1 - 2017/4/12
N2 - 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.
AB - 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.
KW - EGFR
KW - IKKalpha
KW - autoimmune disease
KW - autoreactive T cells
KW - esophageal squamous cell carcinoma
KW - fungal infection
KW - inflammation
KW - mucosal epithelium
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U2 - 10.1016/j.chom.2017.03.006
DO - 10.1016/j.chom.2017.03.006
M3 - Article
C2 - 28407484
AN - SCOPUS:85017333200
SN - 1931-3128
VL - 21
SP - 478-493.e7
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 4
ER -