Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Eur J Immunol. 2009 Nov;39(11):3010-8. doi: 10.1002/eji.200839154.
An effective Th1 type cell-mediated immune response against cancer cells is critical in limiting cancer progression. Gadd45b, a signaling molecule highly up-regulated during Th1 type responses, is studied for its role in limiting tumor growth. Mouse B16 melanoma cells implanted into Gadd45b(-/-) mice grew faster than those in WT or Gadd45b(+/-) littermate controls. The defect of Gadd45b(-/-) mice in tumor immunosurveillance was attributed to the reduced expression of IFN-gamma, granzyme B, and CCR5 in Gadd45b(-/-) CD8(+) T cells at the tumor site. Activation of p38 MAP kinase, but not ERK or JNK, by either TCR-stimuli or IL-12 and IL-18 is diminished in Gadd45b(-/-) CD8(+) T cells, resulting in reduced production of IFN-gamma. In addition, mRNA of T-bet and Eomes were reduced in Gadd45b(-/-) CD8(+) T cells, supporting a critical role of Gadd45b in shaping the Th1 fate. More importantly, the tumor vaccination, which is effective in WT mice, failed in Gadd45b/Gadd45g doubly deficient mice. Collectively, these data demonstrate that members of the Gadd45 gene family are important for anti-tumor immune responses.
针对癌细胞的有效 Th1 型细胞介导的免疫反应对于限制癌症进展至关重要。Gadd45b 是一种在 Th1 型反应中高度上调的信号分子，其在限制肿瘤生长中的作用正在研究中。植入 Gadd45b(-/-) 小鼠的小鼠 B16 黑色素瘤细胞比 WT 或 Gadd45b(+/-) 同窝对照小鼠中的肿瘤生长更快。Gadd45b(-/-) 小鼠在肿瘤免疫监视中的缺陷归因于 Gadd45b(-/-) CD8(+) T 细胞在肿瘤部位 IFN-γ、颗粒酶 B 和 CCR5 的表达减少。TCR 刺激或 IL-12 和 IL-18 激活 Gadd45b(-/-) CD8(+) T 细胞中的 p38 MAP 激酶，但不激活 ERK 或 JNK，导致 IFN-γ产生减少。此外，Gadd45b(-/-) CD8(+) T 细胞中的 T-bet 和 Eomes 的 mRNA 减少，支持 Gadd45b 在塑造 Th1 命运中的关键作用。更重要的是，在 WT 小鼠中有效的肿瘤疫苗接种在 Gadd45b/Gadd45g 双重缺陷小鼠中失败。总之，这些数据表明 Gadd45 基因家族的成员对于抗肿瘤免疫反应很重要。
