PTEN inhibits IL-2 receptor-mediated expansion of CD4+CD25+ Tregs
PTEN inhibits IL-2 receptor-mediated expansion of CD4+CD25+ Tregs
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DOI：
10.1172/jci28057
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发表时间：
2006-09-01
影响因子：
15.9
通讯作者：
Turka, Laurence A.
中科院分区：
文献类型：
--
作者：
Walsh, Patrick T.;Buckler, Jodi L.;Turka, Laurence A.
利用CD 4（+）CD 25（+）T细胞作为细胞免疫疗法的潜力的最大障碍之一是它们的低增殖表型。我们先前已经表明，TGFAP对IL-2的低增殖反应与下游PI 3 K信号传导缺陷有关。在这里，我们证明，有针对性地删除的脂质磷酸酶PTEN（磷酸酶和张力蛋白同源物10号染色体上删除）调节外周稳态的Tendon在体内，并允许他们的扩展在体外单独响应IL-2。PTEN缺陷不会对胸腺发育或TcB功能产生不利影响，TcB保留了其在体外抑制应答T细胞和在体内预防结肠炎的能力。相反，在PTEN缺陷的T细胞以及活化的CD 4（+）T细胞中，PTEN的再表达抑制IL-2依赖性增殖，证实了PTEN作为IL-2受体信号传导的负调节剂。这些数据表明，PTEN在体外调节T细胞对IL-2的“无变应性”反应和在体内调节Treg稳态，并表明抑制PTEN活性可促进这些细胞的扩增以用于细胞免疫治疗的潜在用途。
One of the greatest barriers against harnessing the potential of CD4(+)CD25(+) Tregs as a cellular immunotherapy is their hypoproliferative phenotype. We have previously shown that the hypoproliferative response of Tregs to IL-2 is associated with defective downstream PI3K signaling. Here, we demonstrate that targeted deletion of the lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome 10) regulates the peripheral homeostasis of Tregs in vivo and allows their expansion ex vivo in response to IL-2 alone. PTEN deficiency does not adversely affect either the thymic development or the function of Tregs, which retain their ability to suppress responder T cells in vitro and prevent colitis in vivo. Conversely, reexpression of PTEN in PTEN-deficient Tregs as well as in activated CD4(+)T cells inhibits IL-2-dependent proliferation, confirming PTEN as a negative regulator of IL-2 receptor signaling. These data demonstrate that PTEN regulates the "anergic" response of Tregs to IL-2 in vitro and Treg homeostasis in vivo and indicate that inhibition of PTEN activity may facilitate the expansion of these cells for potential use in cellular immunotherapy.