THE ABSENCE OF THE TRANSCRIPTION ACTIVATOR TFE3 IMPAIRS ACTIVATION OFB-CELLS IN-VIVO

TFE3 is a ubiquitously expressed member of the TFE3/mi family of basic helix loop helix zipper transcription factors. TFE3 binds to mu E3 si tes located in the immunoglobulin heavy-chain (IgH) intronic enhancer, heavy-chain variable region promoters, the Ig kappa intronic enhancer , and regulatory sites in other genes. To understand the role of TFE3 in Ig expression and lymphoid development, we used embryonic stem (ES) cell-mediated gene targeting and RAG2(-/-) blastocyst complementation to generate mice which lack TFE3 in their B and T lymphocytes. TFE3(- ) ES cells fully reconstitute the B- and T-cell compartments, giving r ise to normal patterns of IgM(+) B220(+) B cells and CD4(+) and CD8(+) T cells. However, TFE3(-) B cells show several defects consistent wit h poor B-cell activation. Serum IgM levels are reduced twofold and IgG and IgA isotypes are reduced three- to sixfold in the TFE3(-) chimera s even though in vitro, the TFE3(-) splenocytes secrete normal levels of all isotypes in response to lipopolysaccharide activation. Peripher al TFE3(-) B cells also shown reduced surface expression of CD23 and C D24 (heat-stable antigen).