PI3K p110delta regulates T-cell cytokine production during primary and secondary immune responses in mice and humans.
PI3K p110delta regulates T-cell cytokine production during primary and secondary immune responses in mice and humans.
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PI3K p110delta在小鼠和人类的原发性和继发性免疫反应期间调节T细胞细胞因子的产生。
DOI：
10.1182/blood-2009-07-232330
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发表时间：
2010-03-18
期刊：
影响因子：
20.3
通讯作者：
Okkenhaug K
中科院分区：
文献类型：
--
作者：
Soond DR;Bjørgo E;Moltu K;Dale VQ;Patton DT;Torgersen KM;Galleway F;Twomey B;Clark J;Gaston JS;Taskén K;Bunyard P;Okkenhaug K
我们之前已经描述了PI 3 K p110δ在幼稚T细胞活化和分化过程中的关键和非冗余作用，目前正在开发p110δ抑制剂用于临床。然而，为了有效地治疗已建立的炎性或自身免疫性疾病，重要的是能够抑制先前激活或记忆T细胞。在这项研究中，使用同种型选择性抑制剂IC 87114，我们表明持续的p110δ活性是IFNγ产生所必需的。此外，p110δ的急性抑制抑制细胞因子的产生并减少小鼠的超敏反应。p110δ是否在人类T细胞中发挥类似的作用尚不清楚。在这里，我们表明，IC 87114有效地阻断了TCR诱导的PI 3 K信号转导的幼稚和效应/记忆人类T细胞。重要的是，IC 87114减少了来自健康和过敏供体以及炎性关节炎患者的记忆T细胞的细胞因子产生。这些研究证实，先前激活的记忆T细胞对p110δ抑制至少与幼稚T细胞一样敏感，并表明小鼠模型准确预测了人类T细胞中的p110δ功能。因此，p110δ抑制剂被考虑用于T细胞介导的自身免疫性和炎性疾病的治疗用途是有充分理由的。
We have previously described critical and non-redundant roles for the PI3K p110δ during the activation and differentiation of naïve T cells and p110δ inhibitors are currently being developed for clinical use. However, to effectively treat established inflammatory or autoimmune diseases it is important to be able to inhibit previously activated or memory T cells. In this study, using the isoform-selective inhibitor IC87114, we show that sustained p110δ activity is required for IFNγ production. Moreover, acute inhibition of p110δ inhibits cytokine production and reduces hypersensitivity responses in mice. Whether p110δ played a similar role in human T cells was unknown. Here we show that IC87114 potently blocked TCR-induced PI3K signaling by both naïve and effector/memory human T cells. Importantly, IC87114 reduced cytokine production by memory T cells from healthy and allergic donors and from inflammatory arthritis patients. These studies establish that previously activated memory T cells are at least as sensitive to p110δ inhibition as naïve T cells and show that mouse models accurately predict p110δ function in human T cells. There is therefore a strong rationale for p110δ inhibitors to be considered for therapeutic use in T cell-mediated autoimmune and inflammatory diseases.
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影响因子：
30.5
作者：
Costello, PS;Gallagher, M;Cantrell, DA
通讯作者：
Cantrell, DA
影响因子：
--
作者：
DOUGADOS, M;VANDERLINDEN, S;ZEIDLER, H
通讯作者：
ZEIDLER, H
影响因子：
8
作者：
Billottet, C.;Grandage, V. L.;Khwaja, A.
通讯作者：
Khwaja, A.
影响因子：
20.3
作者：
Condliffe, AM;Davidson, K;Hawkins, PT
通讯作者：
Hawkins, PT
影响因子：
64.5
作者：
Knight, Zachary A.;Gonzalez, Beatriz;Shokat, Kevan M.
通讯作者：
Shokat, Kevan M.