B-CELLS GENETICALLY DEFICIENT IN THE C-REL TRANSACTIVATION DOMAIN HAVE SELECTIVE DEFECTS IN GERMLINE C-H TRANSCRIPTION AND IG CLASS SWITCHING

The Ig heavy chain locus contains a number of binding sites for the tr anscriptional activator, c-Rel. In this study, we evaluated the capaci ty of B cells from mice made genetically deficient in the C-terminal, transactivation domain of the c-Rel protein (Delta c-Rel) to undergo I g class switching. Flow-cytometric and digestion circularization PCR a nalyses revealed that Delta c-Rel B cells failed to switch to IgG3 in response to LPS alone, or to IgG1 or IgE in response to LPS + IL-4. Th is failure to switch to IgG3 or IgG1 was associated with a correspondi ng loss of germline C-H gamma 3 or C-H gamma 1 RNA. However, the defec tive switching to IgE in Delta c-Rel B cells was associated with norma l levels of germline C-H epsilon RNA relative to control B cells, The ability of Delta c-Rel B cells to switch to IgG1, in response to LPS IL-4, could be restored through the action(s) of additional stimuli, and this was associated with induction of normal levels of germline C- H gamma 1 RNA relative to controls, In contrast, LPS-activated B cells from Delta c-Rel mice underwent normal switching to IgA in the presen ce of TGF-beta, relative to control B cells, This was associated with equivalent steady state levels of germline C-H alpha RNA between the t wo B cell populations, These data are the first to demonstrate a key a nd selective role for c-Rel in the regulation of Ig class switching. F urthermore, distinct differences are revealed in the Ig isotype induct ion profiles of B cells lacking c-Rel activity vs those deficient in p 50/nuclear factor-kappa B.