Autoreactive T Cells and Chronic Fungal Infection Drive Esophageal Carcinogenesis

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

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)478-493.e7
JournalCell Host and Microbe
Volume21
Issue number4
DOIs
StatePublished - Apr 12 2017

Keywords

  • EGFR
  • IKKalpha
  • autoimmune disease
  • autoreactive T cells
  • esophageal squamous cell carcinoma
  • fungal infection
  • inflammation
  • mucosal epithelium

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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