Distinct requirements for the naturally occurring splice forms Stat4α and Stat4β in IL-12 responses

Signal transducer and activator of transcription (Stat)4 is a signaling molecule required for normal responses to interleukin-12 (IL-12) and is critically involved in inflammatory responses. We have isolated an alternatively spliced isoform of Stat4, termed Stat4β, which lacks 44 amino acids at the C-terminus, encompassing the putative transcriptional activation domain. To assess the in vivo roles of these Stat4 isoforms, we generated transgenic Stat4-deficient mice expressing Stat4α or Stat4β. Our results indicate that T-cell-specific expression of Stat4α or Stat4β can mediate many aspects of IL-12 signaling including the differentiation of Th1 cells. However, Stat4α is required for normal levels of IL-12-induced interferon-γ production from Th1 cells. Microarray analysis identified 98 genes induced by both Stat4 isoforms, 32 genes induced only by Stat4α and 29 genes induced only by Stat4β. Some induced genes correlate with specific functions including the ability of Stat4β, but not Stat4α, to mediate IL-12-stimulated proliferation. Thus, Stat4α and Stat4β have distinct roles in mediating responses to IL-12.