Obesity-Induced Metabolic Stress Leads to Biased Effector Memory CD4(+) T Cell Differentiation via PI3K p110δ-Akt-Mediated Signals.
Obesity-Induced Metabolic Stress Leads to Biased Effector Memory CD4(+) T Cell Differentiation via PI3K p110δ-Akt-Mediated Signals.
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DOI：
10.1016/j.cmet.2017.01.008
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发表时间：
2017-03-07
期刊：
影响因子：
29
通讯作者：
Marelli-Berg FM
中科院分区：
文献类型：
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作者：
Mauro C;Smith J;Cucchi D;Coe D;Fu H;Bonacina F;Baragetti A;Cermenati G;Caruso D;Mitro N;Catapano AL;Ammirati E;Longhi MP;Okkenhaug K;Norata GD;Marelli-Berg FM
与肥胖相关的低度全身性炎症导致心血管并发症，部分原因是效应T细胞浸润脂肪和血管组织。导致肥胖期间T细胞分化和组织浸润的信号知之甚少。我们测试了饱和脂肪酸诱导的代谢应激是否影响CD 4 + T细胞的分化和运输模式。在高脂饮食喂养的供体中引发的记忆性CD 4 + T细胞优先迁移到非淋巴样炎症部位，与宿主的代谢状态无关。这是由于在高脂肪饮食喂养的动物中致敏后，CD 4 + T细胞偏向性分化为CD 44 hi-CCR 7 lo-CD 62 Llo-CXCR 3 +-LFA 1+效应记忆样T细胞。在自由生活人群中的肥胖受试者中观察到类似的表型。这种发育偏倚不依赖于CD 4 + T细胞和树突状细胞之间的任何串扰，并且通过CD 4 + T细胞直接暴露于棕榈酸酯介导，导致引发时PI 3 K p110δ-Akt依赖性途径的活化增加。高脂饮食导致炎症效应记忆CD 4 + T细胞的发展PI 3 K p110δ-Akt依赖性通路是这种CD 4+发育偏倚的关键该通路由CD 4 + T细胞直接暴露于棕榈酸酯诱导CD 4+发育偏倚通过PI 3 K p110δ-Akt通路的失活来纠正非淋巴组织的淋巴细胞浸润，包括脂肪和血管组织，是饮食性肥胖慢性炎症的突出特征。Mauro等人发现饱和脂肪酸棕榈酸酯激活PI 3 K p110δ-Akt通路，导致肥胖小鼠和人类在引发后CD 4 + T细胞分化为效应记忆样T细胞。
Low-grade systemic inflammation associated to obesity leads to cardiovascular complications, caused partly by infiltration of adipose and vascular tissue by effector T cells. The signals leading to T cell differentiation and tissue infiltration during obesity are poorly understood. We tested whether saturated fatty acid-induced metabolic stress affects differentiation and trafficking patterns of CD4+ T cells. Memory CD4+ T cells primed in high-fat diet-fed donors preferentially migrated to non-lymphoid, inflammatory sites, independent of the metabolic status of the hosts. This was due to biased CD4+ T cell differentiation into CD44hi-CCR7lo-CD62Llo-CXCR3+-LFA1+ effector memory-like T cells upon priming in high-fat diet-fed animals. Similar phenotype was observed in obese subjects in a cohort of free-living people. This developmental bias was independent of any crosstalk between CD4+ T cells and dendritic cells and was mediated via direct exposure of CD4+ T cells to palmitate, leading to increased activation of a PI3K p110δ-Akt-dependent pathway upon priming. High-fat diet causes development of inflammatory effector memory CD4+ T cells A PI3K p110δ-Akt-dependent pathway is key to this CD4+ developmental bias This pathway is induced by direct exposure of CD4+ T cells to palmitate CD4+ developmental bias is corrected by inactivation of PI3K p110δ-Akt pathway Lymphocyte infiltration of non-lymphoid tissues, including adipose and vascular tissues, is a prominent feature of chronic inflammation in diet obesity. Mauro et al. find that the saturated fatty-acid palmitate activates a PI3K p110δ-Akt pathway leading to CD4+ T cell differentiation into effector memory-like T cells upon priming in obese mice and humans.