T-HELPER TYPE-2 INFLAMMATORY DISEASE IN THE ABSENCE OF INTERLEUKIN-4 AND TRANSCRIPTION FACTOR STAT6

An important signaling pathway for the differentiation of T helper typ e 2 (TH2) cells from uncommitted CD4 T cell precursors is activation o f the STAT6 transcription factor by interleukin 4 (IL-4). The protoonc ogene BCL-6 is also involved in TH2 differentiation, as BCL-6 -/- mice develop an inflammation of the heart and lungs associated with an ove rproduction of TH2 cells. Surprisingly, IL-4 -/- BCL-6 -/- and STAT6 - /- BCL-6 -/- double-mutant mice developed the same TH2-type inflammati on of the heart and lungs as is characteristic of BCL-6 -/- mice. Furt hermore, a TH2 cytokine response developed in STAT6 -/- BCL-6 -/- and IL-4 -/- BCL-6 -/- mice after immunization with a conventional antigen in adjuvant. In contrast to these in vivo findings, STAT6 was require d for the in vitro differentiation of BCL-6 -/- T cells into TH2 cells , BCL-6, a transcriptional repressor that can bind to the same DNA bin ding motifs as STAT transcription factors, seems to regulate TH2 respo nses in vivo by a pathway independent of IL-4 and STAT6.