p38 Mitogen-Activated Protein Kinase/Signal Transducer and Activator of Transcription-3 Pathway Signaling Regulates Expression of Inhibitory Molecules in T Cells Activated by HIV-1-Exposed Dendritic Cells
p38 Mitogen-Activated Protein Kinase/Signal Transducer and Activator of Transcription-3 Pathway Signaling Regulates Expression of Inhibitory Molecules in T Cells Activated by HIV-1-Exposed Dendritic Cells
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DOI：
10.2119/molmed.2012.00103
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发表时间：
2012-08-01
影响因子：
5.7
通讯作者：
Larsson, Marie
中科院分区：
文献类型：
--
作者：
Che, Karlhans Fru;Shankar, Esaki Muthu;Larsson, Marie
1型人类免疫缺陷病毒（HIV - 1）感染增强了T细胞上抑制性分子的表达，导致T细胞功能受损。调节抑制性分子以及随后T细胞功能受损发生的信号通路仍不明确。我们发现，暴露于HIV脉冲树突状细胞（DCs）的自体和同种异体T细胞会上调细胞毒性T淋巴细胞抗原（CTLA - 4）、肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）、淋巴细胞激活基因 - 3（LAG3）、T细胞免疫球蛋白黏蛋白 - 3（TIM - 3）、CD160以及某些与抑制相关的转录因子，如B淋巴细胞诱导成熟蛋白 - 1（BLIMP - 1）、Deltex同源蛋白1（DTX1）和叉头框P3（FOXP3），从而导致T细胞抑制。这种诱导受p38丝裂原活化蛋白激酶/信号转导及转录激活因子3（P38MAPK/STAT3）通路的调节，因为阻断这些通路可显著消除所研究的所有抑制性分子的表达，并使T细胞增殖得以恢复。白细胞介素 - 6（IL - 6）、IL - 10以及已知能激活STAT3信号事件的生长因子都不是STAT3激活的原因。P38MAPK/STAT3通路的参与是明显的，因为这些蛋白在HIV - 1致敏细胞中有更高水平的磷酸化。此外，阻断病毒CD4结合和融合显著降低了DCs对致敏T细胞的负面影响。总之，HIV - 1与DCs的相互作用调节了DCs的功能，使其触发T细胞中P38MAPK/STAT3通路的激活，这是抑制性分子上调的原因。在线网址：http://www.molmed.org doi:10.2119/molmed.2012.00103
Human immunodeficiency virus type 1 (HIV-1) infection enhances the expression of inhibitory molecules on T cells, leading to T-cell impairment. The signaling pathways underlying the regulation of inhibitory molecules and subsequent onset of T-cell impairment remain elusive. We showed that both autologous and allogeneic T cells exposed to HIV-pulsed dendritic cells (DCs) upregulated cytotoxic T-lymphocyte antigen (CTLA-4), tumor-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), lymphocyte-activation gene-3 (LAG3). T-cell immunoglobulin mucin-3 (TIM-3), CD160 and certain suppression-associated transcription factors, such as B-lymphocyte induced maturation protein-1 (BLIMP-1), deltex homolog 1 protein (DTX1) and forkhead box P3 (FOXP3), leading to T-cell suppression. This induction was regulated by p38 mitogen-activated protein kinase/signal transducer and activator of transcription-3 (P38MAPK/STAT3) pathways, because their blockade significantly abrogated expression of all the inhibitory molecules studied and a subsequent recovery in T-cell proliferation. Neither interleukin-6 (IL-6) nor IL-10 nor growth factors known to activate STAT3 signaling events were responsible for STAT3 activation. Involvement of the P38MAPK/STAT3 pathways was evident because these proteins had a higher level of phosphorylation in the HIV-1-primed cells. Furthermore, blockade of viral CD4 binding and fusion significantly reduced the negative effects DCs imposed on primed T cells. In conclusion, HIV-1 interaction with DCs modulated their functionality, causing them to trigger the activation of the P38MAPK/STAT3 pathway in T cells, which was responsible for the upregulation of inhibitory molecules. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00103