The transcriptional repressor BCL6 regulates CXCR3 chemokine and HLA II expression in endothelial cells

IFNγ induces an endothelial pro-immunogenic phenotype through the JAK/STAT1 pathway, which can shape the activation of alloreactive leukocytes in transplant rejection. In immune cells, the DNA binding protein BCL6 controls transcription of inflammatory genes. This study tested if BCL6 modulates IFNγ-induced gene expression in endothelial cells (EC). In vitro, BCL6 was IFNγ-inducible in primary human endothelium, along with CXCR3 chemokines and HLA. BCL6 was also increased in human cardiac transplants during acute rejection, as were HLA II and CXCL9. Knockdown of BCL6 augmented, while overexpression and BTB domain inhibitors (BCL6-BTBi) suppressed, HLA II and CXCR3 chemokine expression but not HLA I. Further, BCL6 had a greater effect on HLA-DR and DP, but was less involved in regulating HLA-DQ expression. The effect correlated with BCL6 binding motifs in or near affected genes. The BCL6 DNA recognition sequence was highly similar to that of STAT1, and BTBi reduced STAT1's transcriptional activity in vitro. Our results show for the first time that BCL6 selectively controls IFNγ-induced endothelial gene expression, advancing our understanding of the endogenous mechanisms regulating donor immunogenicity.