Constitutive activation of Wnt signaling favors generation of memory CD8 T cells.
Constitutive activation of Wnt signaling favors generation of memory CD8 T cells.
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DOI：
10.4049/jimmunol.0901199
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发表时间：
2010-02-01
期刊：
影响因子：
--
通讯作者：
Xue HH
中科院分区：
文献类型：
--
作者：
Zhao DM;Yu S;Zhou X;Haring JS;Held W;Badovinac VP;Harty JT;Xue HH
Tcf-1和Lef-1是典型的Wnt途径的效应转录因子，已知对胸腺细胞的正常发育至关重要。然而，它是否在调节成熟的T细胞激活和T细胞介导的免疫反应中起作用在很大程度上还不清楚。与IL-7Rα和CD62L一样，Tcf-1和Lef-1在T细胞应答过程中呈现动态表达变化，在幼稚T细胞中高表达，在效应性T细胞中低表达，在记忆性T细胞中再次上调。P45 TCF-1亚型的强制表达限制了抗原特异性CD8 T细胞对单核细胞增多性李斯特菌感染的反应。然而，当p45转基因与稳定的β-连环蛋白的异位表达相结合时，产生了更多的抗原特异性记忆CD8T细胞，并增强了产生IL-2的能力。此外，这些记忆CD8T细胞在免疫小鼠再次感染强毒单增李斯特菌时，可扩增为更多的次级效应物，并能更快地清除细菌。此外，在痘苗病毒或淋巴细胞性脉络膜脑膜炎病毒感染的情况下，在P45存在的情况下，产生更多的抗原特异性记忆CD8T细胞，并稳定β-catenin转基因。虽然激活的Wnt信号也导致了抗原特异性记忆CD4T细胞的数量增加，但其功能属性和继发感染后的扩增并未得到改善。因此，在初始免疫过程中，规范的Wnt途径的结构性激活有利于记忆性CD8 T细胞的形成，导致再次遇到相同病原体时的免疫增强。
TCF-1 and LEF-1, the effector transcription factors of the canonical Wnt pathway, are known to be critical for normal thymocyte development. However, it is largely unknown if it has a role in regulating mature T cell activation and T cell-mediated immune responses. Here we demonstrate that like IL-7Rα and CD62L, TCF-1 and LEF-1 exhibit dynamic expression changes during T cell responses, being highly expressed in naïve T cells, downregulated in effector T cells, and upregulated again in memory T cells. Enforced expression of a p45 TCF-1 isoform limited the expansion of antigen-specific CD8 T cells in response to Listeria monocytogenes infection. However, when the p45 transgene was coupled with ectopic expression of stabilized β-catenin, more antigen-specific memory CD8 T cells were generated, with enhanced ability to produce IL-2. Moreover, these memory CD8 T cells expanded to a larger number of secondary effectors and cleared bacteria faster when the immunized mice were rechallenged with virulent L. monocytogenes. Furthermore, in response to vaccinia virus or lymphocytic choriomeningitis virus infection, more antigen-specific memory CD8 T cells were generated in the presence of p45 and stabilized β-catenin transgenes. Although activated Wnt signaling also resulted in larger numbers of antigen-specific memory CD4 T cells, their functional attributes and expansion after the secondary infection were not improved. Thus, constitutive activation of the canonical Wnt pathway favors memory CD8 T cell formation during initial immunization, resulting in enhanced immunity upon second encounter with the same pathogen.
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影响因子：
30.5
作者：
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通讯作者：
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