title: Silencing of B cell receptor signals in human naive B cells.
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 Ca(2+) 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.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, 50931 Köln, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Feldhahn
authors.forename: Ines
authors.initials: I
authors.lastname: Schwering
authors.forename: Sanggyu
authors.initials: S
authors.lastname: Lee
authors.forename: Maria
authors.initials: M
authors.lastname: Wartenberg
authors.forename: Florian
authors.initials: F
authors.lastname: Klein
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Guolin
authors.initials: G
authors.lastname: Zhou
authors.forename: San Ming
authors.initials: SM
authors.lastname: Wang
authors.forename: Janet D
authors.initials: JD
authors.lastname: Rowley
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hescheler
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
authors.forename: Ralf
authors.initials: R
authors.lastname: Küppers
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
mesh_terms: D018952:Antigens, CD34 / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D020869:Gene Expression Profiling; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology
chemical_list: D018952:Antigens, CD34; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell