Abstract
The molecular mechanisms regulating CD8+ cytotoxic T lymphocytes (CTLs) are not fully understood. Here, we show that the peroxisome proliferator-activated receptor ƍ (PPAR-δ) suppresses CTL cytotoxicity by inhibiting RelA DNA binding. Treatment of ApcMin/+ mice with the PPAR-δ agonist GW501516 reduced the activation of normal and tumor-associated intestinal CD8+ T cells and increased intestinal adenoma burden. PPAR-δ knockout or knockdown in CTLs increased their cytotoxicity against colorectal cancer cells, whereas overexpression of PPAR-δ or agonist treatment decreased it. Correspondingly, perforin, granzyme B, and interferon γ (IFN-γ) protein and mRNA levels were higher in PPAR-δ knockout or knockdown CTLs and lower in PPAR-δ overexpressing or agonist-treated CTLs. Mechanistically, we found that PPAR-δ binds to RelA, interfering with RelA-p50 heterodimer formation in the nucleus, thereby inhibiting its DNA binding in CTLs. Thus, PPAR-δ is a critical regulator of CTL effector function.
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