Mycobacterium tuberculosis LprA is a lipoprotein agonist of TLR2 that regulates innate immunity and APC function
Mycobacterium tuberculosis LprA is a lipoprotein agonist of TLR2 that regulates innate immunity and APC function
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DOI：
10.4049/jimmunol.177.1.422
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发表时间：
2006-07-01
影响因子：
4.4
通讯作者：
Harding, Clifford V.
中科院分区：
文献类型：
--
作者：
Pecora, Nicole D.;Gehring, Adam J.;Harding, Clifford V.
TLR 2识别结核分枝杆菌（Mtb）的组分，并通过影响先天性和适应性免疫的APC启动应答。Mtb脂蛋白是一类重要的TLR 2配体，但迄今为止只有两种LpqH和LprG被表征。在这项研究中，我们表征第三结核分枝杆菌脂蛋白，LprA，并确定其对宿主巨噬细胞和树突状细胞的影响。LprA是一种细胞壁相关脂蛋白，在生长缓慢的分枝杆菌外没有同源物。使用耻垢分枝杆菌作为表达宿主，我们纯化了具有和不具有其酰基修饰的6 X His标记的LprA。酰化LprA对人和鼠TLR 2都具有激动剂活性，并诱导TNF-α、IL-10和IL-12的表达。LprA还诱导树突状细胞成熟，如通过CD 40、CD 80和II类MHC（MHC-II）的表达增加所示。在巨噬细胞中，与LprA长时间（24 h）孵育降低了IFN-γ诱导的MHC-II Ag加工和呈递，与观察到的MHC-II表达降低一致（巨噬细胞活力不受影响，LprA不诱导细胞凋亡）。减少MHC-II Ag呈递可能代表用于控制炎症的负反馈机制，其可能被Mtb破坏以用于免疫逃避。因此，Mtb LprA是诱导细胞因子应答并调节APC功能的TLR 2激动剂。
TLR2 recognizes components of Mycobacterium tuberculosis (Mtb) and initiates responses by APCs that influence both innate and adaptive immunity. Mtb lipoproteins are an important class of TLR2 ligand, but only two, LpqH and LprG, have been characterized to date. In this study, we characterize a third Mtb lipoprotein, LprA, and determine its effects on host macrophages and dendritic cells. LprA is a cell wall-associated lipoprotein with no homologs outside the slow-growing mycobacteria. Using Mycobacterium smegmatis as an expression host, we purified 6 X His-tagged LprA both with and without its acyl modifications. Acylated LprA had agonist activity for both human and murine TLR2 and induced expression of TNF-alpha, IL-10, and IL-12. LprA also induced dendritic cell maturation as shown by increased expression of CD40, CD80, and class II MHC (MHC-II). In macrophages, prolonged (24 h) incubation with LprA decreased IFN-gamma-induced MHC-II Ag processing and presentation, consistent with an observed decrease in MHC-II expression (macrophage viability was not affected and apoptosis was not induced by LprA). Reduced MHC-II Ag presentation may represent a negative feedback mechanism for control of inflammation that may be subverted by Mtb for immune evasion. Thus, Mtb LprA is a TLR2 agonist that induces cytokine responses and regulates APC function.