Th17 cells are involved in the immune response against pathogens, autoimmunity, and tumor progression. The differentiation of human Th17 cells requires the upregulation of RORγT, which in human cells is still not well understood. We identified 2 putative binding motifs for specificity protein transcription factors from the specificity protein/Kruppel-like factor family in the promoter of human RORγT and investigated the involvement of specificity proteins in the transcriptional regulation of this gene. To this end, a human lymphocytic cell line and in vitro-differentiated Th17 cells were used in promoter activity assays, in situ mutagenesis, chromatin immunoprecipitation, and real-time RT-PCR assays. In some experiments, specificity protein expression and activity was inhibited by siRNA and mithramycin A. The results showed that the transcription factor specificity protein 2 recognized binding motifs in the human RORγT promoter, which was critical for maintaining expression. Furthermore, specificity protein 2 was necessary for maximum IL-17 expression in in vitro-differentiated Th17 cells. These observations demonstrate the significant role of specificity protein 2 in the regulation of the Th17 signature transcription factor RORγT and the maintenance of the Th17 phenotype. The findings also suggest that specificity protein 2 plays a role in Th17-dependent physiologic and pathologic immune responses and might serve as a potential novel target for their modulation.
Keywords: RORC; Th17; mithramycin A; specificity protein 2.
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