IL-33 Is a Cell-Intrinsic Regulator of Fitness during Early B Cell Development

J Immunol. 2019 Sep 15;203(6):1457-1467. doi: 10.4049/jimmunol.1900408. Epub 2019 Aug 7.

Abstract

IL-33 is an IL-1 family member protein that is a potent driver of inflammatory responses in both allergic and nonallergic disease. This proinflammatory effect is mediated primarily by extracellular release of IL-33 from stromal cells and binding of the C-terminal domain of IL-33 to its receptor ST2 on targets such as CD4+ Th2 cells, ILC2, and mast cells. Notably, IL-33 has a distinct N-terminal domain that mediates nuclear localization and chromatin binding. However, a defined in vivo cell-intrinsic role for IL-33 has not been established. We identified IL-33 expression in the nucleus of progenitor B (pro-B) and large precursor B cells in the bone marrow, an expression pattern unique to B cells among developing lymphocytes. The IL-33 receptor ST2 was not expressed within the developing B cell lineage at either the transcript or protein level. RNA sequencing analysis of wild-type and IL-33-deficient pro-B and large precursor B cells revealed a unique, IL-33-dependent transcriptional profile wherein IL-33 deficiency led to an increase in E2F targets, cell cycle genes, and DNA replication and a decrease in the p53 pathway. Using mixed bone marrow chimeric mice, we demonstrated that IL-33 deficiency resulted in an increased frequency of developing B cells via a cell-intrinsic mechanism starting at the pro-B cell stage paralleling IL-33 expression. Finally, IL-33 was detectable during early B cell development in humans and IL33 mRNA expression was decreased in B cell chronic lymphocytic leukemia samples compared with healthy controls. Collectively, these data establish a cell-intrinsic, ST2-independent role for IL-33 in early B cell development.

Publication types

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

MeSH terms

  • Adult
  • Animals
  • B-Lymphocytes / immunology*
  • DNA Replication / immunology
  • Female
  • Humans
  • Interleukin-33 / immunology*
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology
  • Male
  • Mast Cells / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • RNA, Messenger / immunology
  • Signal Transduction / immunology
  • Th2 Cells / immunology
  • Tumor Suppressor Protein p53 / immunology

Substances

  • IL33 protein, human
  • Il33 protein, mouse
  • Interleukin-33
  • RNA, Messenger
  • Tumor Suppressor Protein p53