IL-33 is a cell-intrinsic regulator of fitness during early B cell development

Matthew T. Stier, Ramkrishna Mitra, Lindsay E. Nyhoff, Kasia Goleniewska, Jian Zhang, Matthew V. Puccetti, Holly C. Casanova, Adam C. Seegmiller, Dawn C. Newcomb, Peggy L. Kendall, Christine M. Eischen, R. Stokes Peebles

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

IL-33 is an IL-1 familymember 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 fromstromal 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 cellintrinsic, ST2-independent role for IL-33 in early B cell development.

Original languageEnglish
Pages (from-to)1457-1467
Number of pages11
JournalJournal of Immunology
Volume203
Issue number6
DOIs
StatePublished - Sep 15 2019

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