STAT6 IS REQUIRED FOR IL-4-INDUCED GERMLINE IG GENE-TRANSCRIPTION ANDSWITCH RECOMBINATION

Transcription of the germline C gamma 1 and C epsilon Ig genes is beli eved to be a necessary prerequisite for isotype switching to IgG1 and IgE, respectively. IL-4 stimulation and ligation of CD40 can each inde pendently induce low level germline gamma 1 and epsilon transcription in murine B cells. Together these signals act synergistically to promo te high level germline transcription and are normally required for T-d ependent isotype switching to IgG4 and IgE, The STAT6 transcription fa ctor has been suggested to play a critical role in IL-4-induced activa tion of germline C gamma 1 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 det ectable levels of germline gamma 1 or epsilon transcripts in STAT6-def icient B cells, Germline transcript expression induced by CD40 stimula tion alone is unaffected, but synergism between CD40- and IL-4R-mediat ed signals is completely ablated. Switch recombination to S gamma 1, a s measured by digestion-circularization PCR, is dramatically reduced i n STAT6-deficient B cells stimulated with CD40 ligand plus IL-4, Simil arly, germline gamma 1 transcript expressions and switch recombination to S gamma 1 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 c ritical role for STAT6 in the IL-4-mediated activation of germline Ig gene transcription and switch recombination in nontransformed B cells.