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T helper 17 (Th17) cells specifically transcribe the
Il17
and
Il17f
genes, which are localized in the same chromosome region, but the underlying mechanism is unclear. Here, we report a
cis
element that we previously named conserved noncoding sequence 2 (CNS2), physically interacted with both
Il17
and
Il17f
gene promoters and was sufficient for regulating their selective transcription in Th17 cells. Targeted deletion of CNS2 resulted in impaired retinoic acid-related orphan receptor gamma (RORγ)-driven IL-17 expression
in vitro
. CNS2-deficient T cells also produced substantially decreased amounts of IL-17F. These cytokine defects were associated with defective chromatin remodeling in the
Il17-Il17f
gene locus, possibly due to effects on CNS2-mediated recruitment of histone modifying enzymes p300 and JmjC domain-containing protein 3 (JMJD3). CNS2-deficient animals were also shown to be resistant to experimental autoimmune encephalomyelitis (EAE). Our results thus suggest that CNS2 is sufficient and necessary for
Il17
and optimal
Il17f
gene transcription in Th17 cells.