Seoul Virus-Infected Rat Lung Endothelial Cells and Alveolar Macrophages Differ in Their Ability To Support Virus Replication and Induce Regulatory T Cell Phenotypes
Seoul Virus-Infected Rat Lung Endothelial Cells and Alveolar Macrophages Differ in Their Ability To Support Virus Replication and Induce Regulatory T Cell Phenotypes
复制标题
DOI：
10.1128/jvi.01233-12
复制
发表时间：
2012-11-01
影响因子：
5.4
通讯作者：
Klein, Sabra L.
中科院分区：
文献类型：
--
作者：
Li, Wei;Klein, Sabra L.
汉坦病毒在宿主体内引起持续感染，这归因于调节反应的上调和促炎反应的下调。为了确定大鼠肺泡巨噬细胞(AM)和肺微血管内皮细胞(LMVECs)是否支持首尔病毒(SEOV)复制，并有助于诱导CD4(+)T细胞分化为调节性T(Treg)细胞表型，模拟培养的大鼠AM和LMVECs感染SEOV，分析病毒复制、细胞因子和趋化因子反应以及与T细胞激活相关的细胞表面标记的表达。将同种异基因的CD4(+)T细胞与SEOV感染或模拟感染的AM或LMVECs共培养，分析辅助性T细胞(即Treg、Th17、Th1和Th2)的表达和Treg细胞的频率。感染后两种细胞均可检测到SEOV RNA和感染颗粒，但LMVECs的感染水平高于AM。SEOV感染对上述两种细胞的干扰素β、CCL5、CxCl10及表面主要组织相容性复合体II类(MHC-II)和MHC-I的表达均无影响。SEOV感染可显著增加肺泡巨噬细胞转化生长因子βmRNA和肺内皮细胞程序性死亡1配体1(PD-L1)的表达。SEOV感染的LMVECs诱导同种异体CD4(+)T细胞Foxp3表达和Treg细胞频率显著增加，这是病毒复制和细胞接触依赖的。这些数据表明，除了支持病毒复制外，AM和LMVEC还通过增加转化生长因子β、PD-L1和Treg细胞的活性来创造调节环境，在汉坦病毒的持久性中发挥着不同的作用。
Hantaviruses cause a persistent infection in reservoir hosts that is attributed to the upregulation of regulatory responses and downregulation of proinflammatory responses. To determine whether rat alveolar macrophages (AMs) and lung microvascular endothelial cells (LMVECs) support Seoul virus (SEOV) replication and contribute to the induction of an environment that polarizes CD4(+) T cell differentiation toward a regulatory T (Treg) cell phenotype, cultured primary rat AMs and LMVECs were mock infected or infected with SEOV and analyzed for viral replication, cytokine and chemokine responses, and expression of cell surface markers that are related to T cell activation. Allogeneic CD4(+) T cells were cocultured with SEOV-infected or mock-infected AMs or LMVECs and analyzed for helper T cell (i.e., Treg, Th17, Th1, and Th2) marker expression and Treg cell frequency. SEOV RNA and infectious particles in culture media were detected in both cell types, but at higher levels in LMVECs than in AMs postinfection. Expression of Ifn beta, Ccl5, and Cxcl10 and surface major histocompatibility complex class II (MHC-II) and MHC-I was not altered by SEOV infection in either cell type. SEOV infection significantly increased Tgf beta mRNA in AMs and the amount of programmed cell death 1 ligand 1 (PD-L1) in LMVECs. SEOV-infected LMVECs, but not AMs, induced a significant increase in Foxp3 expression and Treg cell frequency in allogeneic CD4(+) T cells, which was virus replication and cell contact dependent. These data suggest that in addition to supporting viral replication, AMs and LMVECs play distinct roles in hantavirus persistence by creating a regulatory environment through increased Tgf beta, PD-L1, and Treg cell activity.