Tumor Progression Locus 2 (Tpl2) Activates the Mammalian Target of Rapamycin (mTOR) Pathway, Inhibits Forkhead Box P3 (FoxP3) Expression, and Limits Regulatory T Cell (Treg) Immunosuppressive Functions
Tumor Progression Locus 2 (Tpl2) Activates the Mammalian Target of Rapamycin (mTOR) Pathway, Inhibits Forkhead Box P3 (FoxP3) Expression, and Limits Regulatory T Cell (Treg) Immunosuppressive Functions
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DOI：
10.1074/jbc.m116.718783
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发表时间：
2016-08-05
影响因子：
4.8
通讯作者：
Watford, Wendy T.
中科院分区：
文献类型：
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作者：
Li, Xin;Acuff, Nicole V.;Watford, Wendy T.
丝氨酸/苏氨酸激酶肿瘤进展基因座2（Tpl 2，也称为Map 3 k8/Cot）是驱动TNF α、IL-1 β和IFN γ产生的有效炎症介质。我们先前证明了Tpl 2调节T细胞受体（TCR）信号传导并调节T辅助细胞分化。然而，关于Tpl 2如何调节调节性T细胞（Tcells）的发育知之甚少。T细胞是表达FoxP 3的T细胞的专门子集，具有免疫抑制特性以限制过度炎症。由于记录了Tp 12在促进炎症中的作用，我们假设Tp 12拮抗Treg发育和免疫抑制功能。在这里，我们证明了Tp 12抑制诱导型Tp 12的发展。Tp 12（-/-）初始CD 4（+）T细胞在体外以及在卵清蛋白（OVA）诱导的全身耐受的鼠模型中体内优先发育成FoxP 3（+）诱导型T细胞。Tp 12（-/-）T细胞的Treg偏向依赖于TCR信号强度，并且与雷帕霉素（mTOR）途径的哺乳动物靶标的活化降低相对应。重要的是，Tp 12（-/-）Tp 13具有FoxP 3和免疫抑制分子、IL-10和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）的基础增加的表达。此外，它们在结肠炎的T细胞转移模型中具有更强的体内免疫抑制作用，如通过减少效应T细胞积累、炎性细胞因子的全身产生和结肠炎症所证明的。这些结果表明，Tpl 2部分地通过抑制FoxP 3表达和Treg免疫抑制功能来促进炎症。总的来说，这些发现表明Tpl 2抑制可用于优先驱动Treg诱导，从而限制各种自身免疫性疾病中的炎症。
The serine/threonine kinase tumor progression locus 2 (Tpl2, also known as Map3k8/Cot) is a potent inflammatory mediator that drives the production of TNF alpha, IL-1 beta, and IFN gamma. We previously demonstrated that Tpl2 regulates T cell receptor (TCR) signaling and modulates T helper cell differentiation. However, very little is known about how Tpl2 modulates the development of regulatory T cells (Tregs). Tregs are a specialized subset of T cells that express FoxP3 and possess immunosuppressive properties to limit excess inflammation. Because of the documented role of Tpl2 in promoting inflammation, we hypothesized that Tpl2 antagonizes Treg development and immunosuppressive function. Here we demonstrate that Tpl2 constrains the development of inducible Tregs. Tpl2(-/-) naive CD4(+) T cells preferentially develop into FoxP3(+) inducible Tregs in vitro as well as in vivo in a murine model of ovalbumin (OVA)-induced systemic tolerance. Treg biasing of Tpl2(-/-) T cells depended on TCR signal strength and corresponded with reduced activation of the mammalian target of rapamycin (mTOR) pathway. Importantly, Tpl2(-/-) Tregs have basally increased expression of FoxP3 and immunosuppressive molecules, IL-10 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Furthermore, they were more immunosuppressive in vivo in a T cell transfer model of colitis, as evidenced by reduced effector T cell accumulation, systemic production of inflammatory cytokines, and colonic inflammation. These results demonstrate that Tpl2 promotes inflammation in part by constraining FoxP3 expression and Treg immunosuppressive functions. Overall, these findings suggest that Tpl2 inhibition could be used to preferentially drive Treg induction and thereby limit inflammation in a variety of autoimmune diseases.