Pharmacological inhibition of TPL2/MAP3K8 blocks human cytotoxic T lymphocyte effector functions.
Pharmacological inhibition of TPL2/MAP3K8 blocks human cytotoxic T lymphocyte effector functions.
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DOI：
10.1371/journal.pone.0092187
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Farrar JD
中科院分区：
文献类型：
--
作者：
Chowdhury FZ;Estrada LD;Murray S;Forman J;Farrar JD
CD8 + 细胞毒性T淋巴细胞（CTLs）在抵御胞内病原体中起主要作用。在发育过程中，抗原呈递细胞分泌先天性细胞因子，如白细胞介素 - 12（IL - 12）和干扰素 -α（IFN -α），它们促使CTL分化为不同的效应细胞群和长寿记忆细胞群。通过全转录组分析，发现丝氨酸/苏氨酸蛋白激酶Tpl2/MAP3K8受IL - 12诱导，并由效应记忆（TEM）CTL选择性表达。Tpl2通过激活先天性免疫细胞（如巨噬细胞和树突状细胞）中由ERK介导的MAP激酶通路来调节各种炎症通路。在本研究中，我们发现一种特定的小分子Tpl2抑制剂可阻断人CTL的干扰素 -γ（IFN -γ）和肿瘤坏死因子 -α（TNF -α）分泌以及细胞溶解活性。该通路对人效应CTL具有特异性，因为Tpl2抑制剂不会阻断鼠效应CTL的IFN -γ和TNF -α分泌。此外，IL - 12无法诱导鼠CTL中Tpl2的表达，并且Tpl2缺陷型鼠CTL在体外或体内对单核细胞增生李斯特菌感染的应答中均未表现出任何功能缺陷。总之，我们确定了Tpl2在人CTL效应功能中的种属特异性作用，它在针对胞内病原体和肿瘤的适应性免疫应答中起主要作用。
CD8+ cytotoxic T lymphocytes (CTLs) play a major role in defense against intracellular pathogens. During development, antigen-presenting cells secrete innate cytokines such as IL-12 and IFN-α, which drive CTL differentiation into diverse populations of effector and long-lived memory cells. Using whole transcriptome analyses, the serine/threonine protein kinase Tpl2/MAP3K8 was found to be induced by IL-12 and selectively expressed by effector memory (TEM) CTLs. Tpl2 regulates various inflammatory pathways by activating the ERK mediated MAP kinase pathway in innate immune cells such as macrophages and dendritic cells. In this study, we found that a specific small molecule Tpl2 inhibitor blocked IFN-γ and TNF-α secretion as well as cytolytic activity of human CTLs. This pathway was specific for human effector CTLs, as the Tpl2 inhibitor did not block IFN-γ and TNF-α secretion from murine effector CTLs. Further, IL-12 failed to induce expression of Tpl2 in murine CTLs, and Tpl2 deficient murine CTLs did not exhibit any functional deficiency either in vitro or in vivo in response to L. monocytogenes infection. In summary, we identified a species-specific role for Tpl2 in effector function of human CTLs, which plays a major role in adaptive immune responses to intracellular pathogens and tumors.
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影响因子：
2.3
作者：
Lindstrom, Tamsin M.;Robinson, William H.
通讯作者：
Robinson, William H.
影响因子：
4.4
作者：
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影响因子：
7.5
作者：
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通讯作者：
Cohen, Philip
影响因子：
2
作者：
Hirata, Kazuya;Miyashiro, Masahiko;Sugita, Takahisa
通讯作者：
Sugita, Takahisa
DOI：
10.1073/pnas.90.6.2251
发表时间：
1993-03-15
影响因子：
11.1
作者：
PATRIOTIS, C;MAKRIS, A;TSICHLIS, PN
通讯作者：
TSICHLIS, PN