Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2015 Dec 1;112(48):E6644-53. doi: 10.1073/pnas.1514191112. Epub 2015 Nov 16.

Murine germinal center B cells require functional Fms-like tyrosine kinase 3 signaling for IgG1 class-switch recombination.

Author information

1
Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Gothenburg, Gothenburg 41346, Sweden; mattias.svensson@rheuma.gu.se.
2
Department of Rheumatology and Inflammation Research at Sahlgrenska Academy, University of Gothenburg, Gothenburg 41346, Sweden;
3
Department of Microbiology and Immunology at Sahlgrenska Academy, University of Gothenburg, Gothenburg 41390, Sweden.

Abstract

Switched antibody classes are important for efficient immune responses. Aberrant antibody production to otherwise harmless antigens may result in autoimmunity. The protein kinase fms-like tyrosine kinase 3 receptor (Flt3) has an important role during early B-cell development, but the role of Flt3 in peripheral B cells has not been assessed before. Herein we describe a previously unappreciated role for Flt3 in IgG1 class-switch recombination (CSR) and production. We show that Flt3 is reexpressed on B-cell lymphoma 6(+) germinal center B cells in vivo and following LPS activation of peripheral B cells in vitro. Absence of Flt3 signaling in Flt3 ligand-deficient mice results in impaired IgG1 CSR and accumulation of IgM-secreting plasma cells. On activated B cells, Flt3 is coexpressed and functions in synergy with the common-gamma chain receptor family. B cells from Flt3 ligand-deficient mice have impaired IL-4R signaling, with reduced phosphorylation of signal transducer and activator of transcription (Stat) 6, and demonstrate a failure to initiate CSR to IgG1 with low expression of γ1 germ-line transcripts, resulting in impaired IgG1 production. Thus, functional synergy between Flt3 and IL-4R signaling is critical for Stat-mediated regulation of sterile γ1 germ-line transcripts and CSR to IgG1.

KEYWORDS:

Flt3; IL-4R; IgG1; class-switch recombination; germinal center B cells

PMID:
26627255
PMCID:
PMC4672832
DOI:
10.1073/pnas.1514191112
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center