Silencing of B cell receptor signals in human naive B cells

Niklas Feldhahn, Ines Schwering, Sanggyu Lee, Maria Wartenberg, Florian Klein, Hui Wang, Guolin Zhou, San Ming Wang, Janet D. Rowley, Jürgen Hescheler, Martin Krönke, Klaus Rajewsky, Ralf Küppers, Markus Müschen

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

To identify changes in the regulation of B cell receptor (BCR) signals during the development of human B cells, we generated genome-wide gene expression profiles using the serial analysis of gene expression (SAGE) technique for CD34+ hematopoietic stem cells (HSCs), pre-B cells, naive, germinal center (GC), and memory B cells. Comparing these SAGE profiles, genes encoding positive regulators of BCR signaling were expressed at consistently lower levels in naive B cells than in all other B cell subsets. Conversely, a large group of inhibitory signaling molecules, mostly belonging to the immunoglobulin superfamily (IgSF), were specifically or predominantly expressed in naive B cells. The quantitative differences observed by SAGE were corroborated by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry. In a functional assay, we show that down-regulation of inhibitory IgSF receptors and increased responsiveness to BCR stimulation in memory as compared with naive B cells at least partly results from interleukin (IL)-4 receptor signaling. Conversely, activation or impairment of the inhibitory IgSF receptor LIRB1 affected BCR-dependent Ca2- mobilization only in naive but not memory B cells. Thus, LIRB1 and IL-4 may represent components of two nonoverlapping gene expression programs in naive and memory B cells, respectively: in naive B cells, a large group of inhibitory IgSF receptors can elevate the BCR signaling threshold to prevent these cells from premature activation and clonal expansion before GC-dependent affinity maturation. In memory B cells, facilitated responsiveness upon reencounter of the immunizing antigen may result from amplification of BCR signals at virtually all levels of signal transduction.

Original languageEnglish (US)
Pages (from-to)1291-1305
Number of pages15
JournalJournal of Experimental Medicine
Volume196
Issue number10
DOIs
StatePublished - Nov 18 2002

Keywords

  • B cell receptor
  • IL-4
  • ITIM
  • Memory B cells
  • SAGE

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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