Fibroblast-derived IL-33 is dispensable for lymph node homeostasis but critical for CD8 T-cell responses to acute and chronic viral infection

Eur J Immunol. 2021 Jan;51(1):76-90. doi: 10.1002/eji.201948413. Epub 2020 Aug 5.


Upon viral infection, stressed or damaged cells can release alarmins like IL-33 that act as endogenous danger signals alerting innate and adaptive immune cells. IL-33 coming from nonhematopoietic cells has been identified as important factor triggering the expansion of antiviral CD8+ T cells. In LN the critical cellular source of IL-33 is unknown, as is its potential cell-intrinsic function as a chromatin-associated factor. Using IL-33-GFP reporter mice, we identify fibroblastic reticular cells (FRC) and lymphatic endothelial cells (LEC) as the main IL-33 source. In homeostasis, IL-33 is dispensable as a transcriptional regulator in FRC, indicating it functions mainly as released cytokine. Early during infection with lymphocytic choriomeningitis virus (LCMV) clone 13, both FRC and LEC lose IL-33 protein expression suggesting cytokine release, correlating timewise with IL-33 receptor expression by reactive CD8+ T cells and their greatly augmented expansion in WT versus ll33-/- mice. Using mice lacking IL-33 selectively in FRC versus LEC, we identify FRC as key IL-33 source driving acute and chronic antiviral T-cell responses. Collectively, these findings show that LN T-zone FRC not only regulate the homeostasis of naïve T cells but also their expansion and differentiation several days into an antiviral response.

Keywords: FRC; Interleukin-33; LCMV; alarmin; fibroblastic reticular cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adaptive Immunity
  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Chronic Disease
  • Endothelial Cells / immunology
  • Fibroblasts / immunology
  • Homeostasis
  • Humans
  • Immunity, Innate
  • Interleukin-33 / deficiency
  • Interleukin-33 / genetics
  • Interleukin-33 / metabolism*
  • Lymph Nodes / immunology
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic choriomeningitis virus / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Immunological


  • IL33 protein, human
  • Il33 protein, mouse
  • Interleukin-33