STAT6 is required for IL-4-induced germline Ig gene transcription and switch recombination.
Transcription of the germline C gamma1 and C epsilon Ig genes is believed to be a necessary prerequisite for isotype switching to IgG1 and IgE, respectively. IL-4 stimulation and ligation of CD40 can each independently induce low level germline gamma1 and epsilon transcription in murine B cells. Together these signals act synergistically to promote high level germline transcription and are normally required for T-dependent isotype switching to IgG1 and IgE. The STAT6 transcription factor has been suggested to play a critical role in IL-4-induced activation of germline C gamma1 and C epsilon genes. To directly assess the role of STAT6 in IL-4R- and CD40-mediated germline transcription and switching, we have analyzed these events in splenic B cells from STAT6-deficient mice. Our results demonstrate that IL-4 does not induce detectable levels of germline gamma1 or epsilon transcripts in STAT6-deficient B cells. Germline transcript expression induced by CD40 stimulation alone is unaffected, but synergism between CD40- and IL-4R-mediated signals is completely ablated. Switch recombination to S gamma1, as measured by digestion-circularization PCR, is dramatically reduced in STAT6-deficient B cells stimulated with CD40 ligand plus IL-4. Similarly, germline gamma1 transcript expression and switch recombination to S gamma1 are also impaired in STAT6-deficient B cells stimulated with IL-4, IL-5, and anti-IgD Abs conjugated to dextran, a model for T-independent type II responses. These results directly demonstrate a critical role for STAT6 in the IL-4-mediated activation of germline Ig gene transcription and switch recombination in nontransformed B cells.
Linehan
L A
LA
Department of Microbiology, University of Texas Health Science Center, San Antonio 78284, USA.
Warren
W D
WD
Thompson
P A
PA
Grusby
M J
MJ
Berton
M T
MT
D000818:Animals; D000955:Antigens, T-Independent / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000502:physiology; D023201:CD40 Ligand; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D005803:Genes, Immunoglobulin; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000235:genetics; D007139:Immunoglobulin epsilon-Chains / Q000235:genetics; D007142:Immunoglobulin gamma-Chains / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050800:STAT6 Transcription Factor; D013601:T-Lymphocytes / Q000276:immunology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000276:immunology*
D000955:Antigens, T-Independent; D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D007139:Immunoglobulin epsilon-Chains; D007142:Immunoglobulin gamma-Chains; D008024:Ligands; D008562:Membrane Glycoproteins; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D023201:CD40 Ligand; D015847:Interleukin-4