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

J Autoimmun. 2020 Mar;108:102422. doi: 10.1016/j.jaut.2020.102422. Epub 2020 Feb 4.

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.

Keywords: Autoimmune disease; Cytotoxic T lymphocytes; IFNβ; IL-15; IL-21; Intraepithelial lymphocytes; Tissue-resident lymphocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alarmins / metabolism*
  • Autoimmunity
  • Celiac Disease / etiology
  • Celiac Disease / metabolism
  • Celiac Disease / pathology
  • Cytokines / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Humans
  • Inflammatory Bowel Diseases / etiology
  • Inflammatory Bowel Diseases / metabolism
  • Inflammatory Bowel Diseases / pathology
  • Interleukin-15 / metabolism
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Intraepithelial Lymphocytes / immunology*
  • Intraepithelial Lymphocytes / metabolism*
  • Promoter Regions, Genetic
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism*

Substances

  • Alarmins
  • Cytokines
  • IL15 protein, human
  • Interleukin-15