Flt3 Ligand Treatment Attenuates T Cell Dysfunction and Improves Survival in a Murine Model of Burn Wound Sepsis.
Flt3 Ligand Treatment Attenuates T Cell Dysfunction and Improves Survival in a Murine Model of Burn Wound Sepsis.
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DOI：
10.1097/shk.0000000000000688
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发表时间：
2017-01
期刊：
影响因子：
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通讯作者：
Sherwood ER
中科院分区：
文献类型：
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作者：
Patil NK;Bohannon JK;Luan L;Guo Y;Fensterheim B;Hernandez A;Wang J;Sherwood ER
脓毒症是严重烧伤患者死亡的主要原因。烧伤会破坏保护皮肤的屏障，并导致免疫功能障碍。在我们之前的研究中，我们发现烧伤和伤口感染导致淋巴细胞数量显著下降，这意味着适应性免疫系统功能障碍。在本研究中，我们在烧伤创面脓毒症模型中观察了FMS如酪氨酸激酶-3配体(Flt3L)对T细胞表型和功能的影响。FLt3L是造血祖细胞发育和扩增髓系和淋巴系所必需的细胞因子。Flt3L可增强烧伤创面脓毒症时树突状细胞和中性粒细胞的天然免疫功能。然而，Flt3L在烧伤创面脓毒症期间改善T细胞功能的能力之前还没有得到评估。小鼠造成35%总体表面积烫伤，从烫伤后1天开始每天经腹膜途径给予Flt3L(10μg)或赋形剂治疗。烧伤后第4天用铜绿假单胞菌诱导创面感染。用流式细胞仪检测脾和创面引流淋巴结中的白细胞。还评估了细菌清除、器官损伤和生存情况。Flt3L治疗可预防烧伤和感染引起的脾组织中CD4+和CD8+T细胞的下降。Flt3L治疗还可减轻小鼠脾和创面引流淋巴结CD8+T细胞分泌干扰素γ的作用。此外，Flt3L还可降低小鼠脾树突状细胞和巨噬细胞程序性死亡配体1(PD-L1)的表达水平。Flt3治疗改善了全身细菌清除，减少了肝和肾损伤，并显著提高了烧伤创面脓毒症小鼠的存活率。烧伤和相关的脓毒症会导致T细胞的显著损失和T细胞功能障碍的证据。Flt3L可减轻小鼠T细胞功能障碍，提高宿主对烧伤创面败血症的抵抗力。
Sepsis is a leading cause of death among severely burned patients. Burn injury disrupts the protective skin barrier and causes immunological dysfunction. In our previous studies, we found that burn injury and wound infection causes a significant decline in lymphocyte populations, implying adaptive immune system dysfunction. In the present study, we examined the effect of treatment with Fms like tyrosine kinase-3 Ligand (Flt3L) on T cell phenotype and function in a model of burn wound sepsis. FLt3L is an essential cytokine required for hematopoietic progenitor cell development and expansion of both myeloid and lymphoid lineages. Flt3L has been shown to potentiate innate immune functions of dendritic cells and neutrophils during burn wound sepsis. However, the ability of Flt3L to improve T cell function during burn wound sepsis has not been previously evaluated. Mice underwent 35% total body surface area scald burn and were treated with Flt3L (10μg) or vehicle daily via the intraperitoneal route starting one day after burn injury. On day 4 after burn injury, Pseudomonas aeruginosa was used to induce wound infection. Leukocytes in spleen and wound draining lymph nodes were characterized using flow cytometry. Bacterial clearance, organ injury and survival were also assessed. Flt3L treatment prevented the decline in splenic CD4+ and CD8+ T cells caused by burn injury and infection. Flt3L treatment also attenuated the decline in CD28 expression on CD4+ and CD8+ T cells and IFNγ production by CD8+ T cells in the spleen and wound draining lymph nodes. Furthermore, Flt3L decreased the levels of programmed death ligand 1 (PD-L1) expression on splenic dendritic cells and macrophages. Flt3 treatment improved systemic bacterial clearance, decreased liver and kidney injury, and significantly improved survival in mice with burn wound sepsis. Burn injury and associated sepsis causes significant loss of T cells and evidence of T cell dysfunction. Flt3L attenuates T cell dysfunction and improves host resistance to burn wound sepsis in mice.