Early Inhibition of Fatty Acid Synthesis Reduces Generation of Memory Precursor Effector T Cells in Chronic Infection.
Early Inhibition of Fatty Acid Synthesis Reduces Generation of Memory Precursor Effector T Cells in Chronic Infection.
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DOI：
10.4049/jimmunol.1602110
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发表时间：
2018-01-15
期刊：
影响因子：
--
通讯作者：
Stephens R
中科院分区：
文献类型：
--
作者：
Ibitokou SA;Dillon BE;Sinha M;Szczesny B;Delgadillo A;Reda Abdelrahman D;Szabo C;Abu-Elheiga L;Porter C;Tuvdendorj D;Stephens R
了解疟疾中CD4记忆T细胞(TMEM)分化的机制对疫苗开发至关重要。然而，CD4TMEM分化的代谢调控尚不清楚，尤其是在持续性感染中。在这项研究中，我们研究了脂肪酸合成(FAS)在查鲍迪疟原虫慢性感染小鼠TMEM发育中的作用。我们发现，T细胞特异性缺失和早期药物抑制乙酰辅酶A羧基酶1(Fas的限速步骤)可以抑制早期记忆前体效应器T细胞(MPEC)的产生。为了比较Fas在慢性感染的TMEM早期分化和存活中的作用，在感染后不同时间给予乙酰辅酶A羧基酶1，5-(十四烷氧基)-2-呋喃甲酸的特异性抑制剂。值得注意的是，只有在T细胞启动过程中Fas被抑制时，TMEM的数量才会减少，但在TMEM存活期不会减少。抑制Fas刺激效应T细胞的增殖，显著降低峰值寄生虫血症，这与改善T细胞的功能是一致的。相反，在慢性但非急性感染中，由于早期Fas抑制，MPEC以T细胞固有的方式减少。感染的早期治愈也增加了TMEM的线粒体体积，与TJeff相比，支持了先前关于急性感染的报道。我们证明，MPEC的特异性作用是由于MPEC中的脂肪酸含量和合成比终末分化的TEFF更高。综上所述，CD4T细胞上的Fas调节了慢性感染早期TMEM和TJeff的分化。
Understanding the mechanisms of CD4 memory T cell (Tmem) differentiation in malaria is critical for vaccine development. However, the metabolic regulation of CD4 Tmem differentiation is not clear, particularly in persistent infections. In this study, we investigated the role of fatty acid synthesis (FAS) in Tmem development in Plasmodium chabaudi chronic mouse malaria infection. We show that T cell-specific deletion, and early pharmaceutical inhibition of acetyl coA carboxylase 1, the rate limiting step of FAS, inhibit generation of early memory precursor effector T cells (MPEC). To compare the role of FAS during early differentiation or survival of Tmem in chronic infection, a specific inhibitor of acetyl coA carboxylase 1, 5-(Tetradecyloxy)-2-furoic acid, was administered at different times postinfection. Strikingly, the number of Tmem was only reduced when FAS was inhibited during T cell priming, but not during the Tmem survival phase. FAS inhibition during priming increased effector T cells (Teff) proliferation, and strongly decreased peak parasitemia, which is consistent with improved Teff function. Conversely, MPEC were decreased, in a T cell-intrinsic manner, upon early FAS inhibition in chronic, but not acute, infection. Early cure of infection also increased mitochondrial volume in Tmem compared to Teff, supporting previous reports in acute infection. We demonstrate that the MPEC-specific effect was due to the higher fatty acid content and synthesis in MPEC compared to terminally differentiated Teff. In conclusion, FAS in CD4 T cells regulates the early divergence of Tmem from Teff in chronic infection.
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影响因子：
6.4
作者：
Gordon EB;Hart GT;Tran TM;Waisberg M;Akkaya M;Skinner J;Zinöcker S;Pena M;Yazew T;Qi CF;Miller LH;Pierce SK
通讯作者：
Pierce SK
影响因子：
64.5
作者：
Chang CH;Curtis JD;Maggi LB Jr;Faubert B;Villarino AV;O'Sullivan D;Huang SC;van der Windt GJ;Blagih J;Qiu J;Weber JD;Pearce EJ;Jones RG;Pearce EL
通讯作者：
Pearce EL
影响因子：
64.8
作者：
Araki, Koichi;Turner, Alexandra P.;Shaffer, Virginia Oliva;Gangappa, Shivaprakash;Keller, Susanne A.;Bachmann, Martin F.;Larsen, Christian P.;Ahmed, Rafi
通讯作者：
Ahmed, Rafi
影响因子：
13.8
作者：
Guan, Kun-Liang;Xiong, Yue
通讯作者：
Xiong, Yue
DOI：
10.4269/tropmed.1999.61-044
发表时间：
1999-07-01
影响因子：
3.3
作者：
Collins, WE;Jeffery, GM
通讯作者：
Jeffery, GM