C/EBPβ controls mucosal fungal immunity through regulation of β-defensins (IRM11P.630)

Th17 cells and IL-17 play essential host-defensive roles in immunity to pathogens, particularly the commensal microbe Candida albicans. Although best known for activation of NF-κB, IL-17 potently activates CCAAT enhancer binding protein transcription factors, which are required for induction of many IL-17 target genes. C/EBPβ is translated into 3 distinct protein isoforms whose expression is regulated by the differential use of different translational initiation start sites, known as LAP* (38kDa), LAP (35kDa) and LIP (22kDa). We have shown that IL-17 induces the alternative translation of C/EBPβ, inducing a marked increase in LAP* and LIP. However, the functional significance of differential C/EBPβ isoform expression remains enigmatic. To determine the biological significance of C/EBPβ alternative translation, we used C/EBPβ-/- mice and a knockin that cannot generate the LAP isoform (C/EBPβM20A). We then assessed susceptibility of these mice to oral C. albicans infection. We found that C/EBPβ-/- but not C/EBPβM20 mice were highly susceptible to disease indicating that LAP is dispensable but C/EBPβ is required. In evaluating a panel of downstream genes to elucidate mechanisms of C/EBPβ-dependent immunity, the gene encoding β-defensin 3 (BD3) was the only IL-17 target gene strongly downregulated in susceptible C/EBPβ-/- mice. These results highlight a key role for C/EBP in antifungal immunity mediated by IL-17 and a previously unrecognized role for C/EBPβ in BD3 expression.