A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels

Wei Luo, Jessica Mayeux, Toni Gutierrez, Lisa Russell, Andrew Getahun, Jennifer Müller, Thomas Tedder, Jane Parnes, Robert Rickert, Lars Nitschke, John Cambier, Anne B. Satterthwaite, Lee Ann Garrett-Sinha

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Signaling through the BCR can drive B cell activation and contribute to B cell differentiation into Ab-secreting plasma cells. The positive BCR signal is counterbalanced by a number of membrane-localized inhibitory receptors that limit B cell activation and plasma cell differentiation. Deficiencies in these negative signaling pathways may cause autoantibody generation and autoimmune disease in both animal models and human patients.We have previously shown that the transcription factor Ets1 can restrain B cell differentiation into plasma cells. In this study, we tested the roles of the BCR and inhibitory receptors in controlling the expression of Ets1 in mouse B cells. We found that Ets1 is downregulated in B cells by BCR or TLR signaling through a pathway dependent on PI3K, Btk, IKK2, and JNK. Deficiencies in inhibitory pathways, such as a loss of the tyrosine kinase Lyn, the phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP1) or membrane receptors CD22 and/or Siglec-G, result in enhanced BCR signaling and decreased Ets1 expression. Restoring Ets1 expression in Lyn- or SHP1-deficient B cells inhibits their enhanced plasma cell differentiation. Our findings indicate that downregulation of Ets1 occurs in response to B cell activation via either BCR or TLR signaling, thereby allowing B cell differentiation and that the maintenance of Ets1 expression is an important function of the inhibitory Lyn → CD22/SiglecG → SHP1 pathway in B cells.

Original languageEnglish (US)
Pages (from-to)909-920
Number of pages12
JournalJournal of Immunology
Volume193
Issue number2
DOIs
StatePublished - Jul 15 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Luo, W., Mayeux, J., Gutierrez, T., Russell, L., Getahun, A., Müller, J., Tedder, T., Parnes, J., Rickert, R., Nitschke, L., Cambier, J., Satterthwaite, A. B., & Garrett-Sinha, L. A. (2014). A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels. Journal of Immunology, 193(2), 909-920. https://doi.org/10.4049/jimmunol.1400666