AP‐1 inhibition enhances the activity of IL‐17 producing cells

Abstract

The activator protein‐1 (AP‐1) transcription factor complex plays a role in the growth, differentiation, and apoptotic responses of mammalian cells. AP‐1 is comprised of basic leucine zipper (bZIP) protein dimers that bind specific DNA sequences to regulate gene transcription. Studies have shown that AP‐1 dimers containing the bZIP protein BATF function as transcriptional inhibitors. In the mouse, endogenous BATF expression is modulated during discrete stages of T cell development, suggesting that genes differentially regulated by BATF are critical to growth decisions in this lineage. Using transgenic mice that overexpress BATF throughout all stages of T cell development (CD2‐HA‐BATF), we show that persistent AP‐1 inhibition leads to a reduced number of natural killer T (NKT) cells. In contrast, we have observed that the Th17 lineage is over‐represented in these same animals. Flow cytometry and ELISA experiments reveal an increase in cell numbers as well as an increase IL‐17 secretion when compared to controls. Real time PCR experiments reveal that transgenic splenocytes show an increase in IL‐17 and IL‐23R mRNA expression, suggesting that naïve CD4+ cells are biased toward the Th17 lineage. Current work is focused on identifying the AP‐1 target genes whose expression is influenced by BATF to generate these intriguing, yet opposing, T cell phenotypes. This work is supported by PHS Awards CA78264 and CA114381.