Malignant Tregs express low molecular splice forms of FOXP3 in Sezary syndrome
Malignant Tregs express low molecular splice forms of FOXP3 in Sezary syndrome
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DOI：
10.1038/leu.2008.224
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发表时间：
2008-12-01
期刊：
影响因子：
11.4
通讯作者：
Woetmann, A.
中科院分区：
文献类型：
--
作者：
Krejsgaard, T.;Gjerdrum, L. M.;Woetmann, A.
Sezary综合征（SS）是皮肤T细胞淋巴瘤的一种侵袭性变异。在疾病进展期间，免疫缺陷发展;然而，潜在的分子和细胞机制尚未完全理解。本文研究了SS中调节性T细胞（Treg）的功能和FOXP 3的表达。我们证明，在15例患者中的8例恶性T细胞染色阳性的抗FOXP 3抗体。蛋白质印迹分析显示FOXP 3的两种低分子剪接形式的表达，但野生型（wt）FOXP 3不表达。恶性T细胞产生白细胞介素-10和TGF-β，并抑制非恶性T细胞的生长。Treg表型和抑制性细胞因子的产生是由Jak 3的异常激活驱动的，与FOXP 3剪接形式无关。与野生型FOXP 3相反，FOXP 3的低分子剪接形式在报道基因测定中对核因子-κ B（NF-κ B）活性没有抑制作用，这与恶性T细胞中的组成型NF-κ B活性一致。总之，我们表明恶性T细胞表达FOXP 3的低分子剪接形式，并作为TcP发挥功能。此外，我们提供的证据表明，FOXP 3剪接形式在功能上与野生型FOXP 3不同，并且不参与抑制功能的执行。因此，这是人类疾病中FOXP 3剪接形式的首次描述。
Sezary syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma. During disease progression, immunodeficiency develops; however, the underlying molecular and cellular mechanisms are not fully understood. Here, we study the regulatory T cell (Treg) function and the expression of FOXP3 in SS. We demonstrate that malignant T cells in 8 of 15 patients stain positive with an anti-FOXP3 antibody. Western blotting analysis shows expression of two low molecular splice forms of FOXP3, but not of wild-type (wt) FOXP3. The malignant T cells produce interleukin-10 and TGF-beta and suppress the growth of non-malignant T cells. The Treg phenotype and the production of suppressive cytokines are driven by aberrant activation of Jak3 independent of the FOXP3 splice forms. In contrast to wt FOXP3, the low molecular splice forms of FOXP3 have no inhibitory effect on nuclear factor-kappa B (NF-kappa B) activity in reporter assays which is in keeping with a constitutive NF-kappa B activity in the malignant T cells. In conclusion, we show that the malignant T cells express low molecular splice forms of FOXP3 and function as Tregs. Furthermore, we provide evidence that FOXP3 splice forms are functionally different from wt FOXP3 and not involved in the execution of the suppressive function. Thus, this is the first description of FOXP3 splice forms in human disease.