Sepsis-Induced Thymic Atrophy Is Associated with Defects in Early Lymphopoiesis
Sepsis-Induced Thymic Atrophy Is Associated with Defects in Early Lymphopoiesis
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DOI：
10.1002/stem.2464
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发表时间：
2016-12-01
期刊：
影响因子：
5.2
通讯作者：
Zeng, Hui
中科院分区：
文献类型：
--
作者：
Kong, Yaxian;Li, Yajie;Zeng, Hui
T淋巴功能受损与适应性免疫反应的免疫抑制有关，并在脓毒症患者和动物模型的发病率和死亡率中发挥作用。尽管先前的研究检查了几种对T淋巴生成产生负面影响的胸腺内机制，但对胸腺外机制的了解仍然很少。在这里，我们报告了三种小鼠脓毒症模型（盲肠结扎和穿刺，脂多糖连续注射和聚I:C连续注射）中早期T谱系祖细胞（ETPs）百分比的急剧下降。然而，脓毒症小鼠的骨髓（BM）前体细胞数量并未减少。相反，ETPs的BM祖细胞表达CC趋化因子受体（CCR） 7、CCR9和p选择素糖蛋白配体1的mRNA水平降低，并且在体外和体内表现出受损的归巢能力。此外，RNA-Seq分析和real-time PCR显示造血干细胞和祖细胞中几个淋巴相关基因明显下调。造血干细胞和祖细胞在体外和体内均分化为骨髓细胞，但不能产生T淋巴细胞。我们的研究结果表明，败血性小鼠中etp的消耗可能是BM祖细胞向胸腺迁移受损的结果，以及淋巴细胞谱系承诺的缺陷。
Impaired T lymphopoiesis is associated with immunosuppression of the adaptive immune response and plays a role in the morbidity and mortality of patients and animal models of sepsis. Although previous studies examined several intrathymic mechanisms that negatively affect T lymphopoiesis, the extrathymic mechanisms remain poorly understood. Here, we report a dramatic decrease in the percentage of early T lineage progenitors (ETPs) in three models of sepsis in mice (cecal ligation and puncture, lipopolysaccharide continuous injection, and poly I:C continuous injection). However, septic mice did not show a decrease in the number of bone marrow (BM) precursor cells. Instead, the BM progenitors for ETPs expressed reduced mRNA levels of CC chemokine receptor (CCR) 7, CCR9 and P-selectin glycoprotein ligand 1, and exhibited impaired homing capacity in vitro and in vivo. Furthermore, RNA-Seq analysis and real-time PCR showed a marked downregulation of several lymphoid-related genes in hematopoietic stem and progenitor cells. Hematopoietic stem and progenitor cells differentiated into myeloid cells but failed to generate T lymphocytes in vitro and in vivo. Our results indicate that the depletion of ETPs in septic mice might be a consequence of an impaired migration of BM progenitors to the thymus, as well as a defect in lymphoid lineage commitment.