Tissue alarmins and adaptive cytokine induce dynamic and distinct transcriptional responses in tissue-resident intraepithelial cytotoxic T lymphocytes

Maria Magdalena Zorro, Raul Aguirre-Gamboa, Toufic Mayassi, Cezary Ciszewski, Donatella Barisani, Shixian Hu, Rinse K. Weersma, Sebo Withoff, Yang Li, Cisca Wijmenga, Bana Jabri*, Iris H Jonkers

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
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Abstract

The respective effects of tissue alarmins interleukin (IL)-15 and interferon beta (IFNβ), and IL-21 produced by T cells on the reprogramming of cytotoxic T lymphocytes (CTLs) that cause tissue destruction in celiac disease is poorly understood. Transcriptomic and epigenetic profiling of primary intestinal CTLs showed massive and distinct temporal transcriptional changes in response to tissue alarmins, while the impact of IL-21 was limited. Only anti-viral pathways were induced in response to all the three stimuli, albeit with differences in dynamics and strength. Moreover, changes in gene expression were primarily independent of changes in H3K27ac, suggesting that other regulatory mechanisms drive the robust transcriptional response. Finally, we found that IL-15/IFNβ/IL-21 transcriptional signatures could be linked to transcriptional alterations in risk loci for complex immune diseases. Together these results provide new insights into molecular mechanisms that fuel the activation of CTLs under conditions that emulate the inflammatory environment in patients with autoimmune diseases.

Original languageEnglish
Article number102422
Number of pages10
JournalJournal of Autoimmunity
Volume108
Early online date4-Feb-2020
DOIs
Publication statusPublished - Mar-2020

Keywords

  • Autoimmune disease
  • Cytotoxic T lymphocytes
  • Intraepithelial lymphocytes
  • IFN beta
  • IL-15
  • IL-21
  • Tissue-resident lymphocytes
  • SUSCEPTIBILITY LOCI
  • GENETIC RISK
  • EFFECTOR CTL
  • CELLS
  • DISEASE
  • IDENTIFICATION
  • ASSOCIATION
  • ARCHITECTURE
  • EXPRESSION
  • IMMUNITY

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