Secreted immunodominant Mycobacterium tuberculosis antigens are processed by the cytosolic pathway.
Secreted immunodominant Mycobacterium tuberculosis antigens are processed by the cytosolic pathway.
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DOI：
10.4049/jimmunol.1000801
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发表时间：
2010-10-01
期刊：
影响因子：
--
通讯作者：
Lewinsohn DM
中科院分区：
文献类型：
--
作者：
Grotzke JE;Siler AC;Lewinsohn DA;Lewinsohn DM
接触结核分枝杆菌可能会导致大多数人终身但无症状感染。尽管在人类和小鼠的感染过程中，CD8+ T 细胞被高频率诱导产生，但 MHC I 类分子如何处理和呈递吞噬体结核分枝杆菌 Ags，人们却知之甚少。概括地说，已经描述了胞质和非胞质途径。我们之前已经表征了来自结核分枝杆菌的三个 HLA-I 表位的呈递，并表明这些 Ag 在细胞质中被加工，而其他人则证明了 19-kDa 脂蛋白的非胞质呈递以及来自结核分枝杆菌感染的细胞的凋亡小体。在本文中，我们现在描述了来自人类树突细胞中四种蛋白质的另外六个结核分枝杆菌表位的加工途径。添加内质网-高尔基体运输抑制剂布雷菲德菌素 A，导致与胞质呈递一致的 Ag 加工完全废除。然而，尽管添加蛋白酶体抑制剂环氧霉素阻断了两个表位的呈递，但四个表位的呈递得到增强。为了进一步检查环氧霉素增强表位的蛋白酶体加工的要求，建立了体外蛋白酶体消化测定法。我们发现蛋白酶体确实产生表位，并且表位产生在环氧霉素存在下增强。为了进一步证实 epoxomicin 抑制的表位和 epoxomicin 增强的表位均在细胞质中进行加工，我们证明了 TAP 转运和新蛋白质合成是呈递所必需的。总而言之，这些数据表明免疫显性结核分枝杆菌 CD8+ Ags 使用胞质途径进行加工和呈递。
Exposure to Mycobacterium tuberculosis can result in lifelong but asymptomatic infection in most individuals. Although CD8+ T cells are elicited at high frequencies over the course of infection in both humans and mice, how phagosomal M. tuberculosis Ags are processed and presented by MHC class I molecules is poorly understood. Broadly, both cytosolic and noncytosolic pathways have been described. We have previously characterized the presentation of three HLA-I epitopes from M. tuberculosis and shown that these Ags are processed in the cytosol, whereas others have demonstrated noncytosolic presentation of the 19-kDa lipoprotein as well as apoptotic bodies from M. tuberculosis-infected cells. In this paper, we now characterize the processing pathway in an additional six M. tuberculosis epitopes from four proteins in human dendritic cells. Addition of the endoplasmic reticulum-Golgi trafficking inhibitor, brefeldin A, resulted in complete abrogation of Ag processing consistent with cytosolic presentation. However, although addition of the proteasome inhibitor epoxomicin blocked the presentation of two epitopes, presentation of four epitopes was enhanced. To further examine the requirement for proteasomal processing of an epoxomicin-enhanced epitope, an in vitro proteasome digestion assay was established. We find that the proteasome does indeed generate the epitope and that epitope generation is enhanced in the presence of epoxomicin. To further confirm that both the epoxomicin-inhibited and epoxomicin-enhanced epitopes are processed cytosolically, we demonstrate that TAP transport and new protein synthesis are required for presentation. Taken together, these data demonstrate that immunodominant M. tuberculosis CD8+ Ags are processed and presented using a cytosolic pathway.
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影响因子：
6.7
作者：
Lewinsohn, Deborah A;Winata, Ervina;Swarbrick, Gwendolyn M;Tanner, Katie E;Cook, Matthew S;Null, Megan D;Cansler, Meghan E;Sette, Alessandro;Sidney, John;Lewinsohn, David M
通讯作者：
Lewinsohn, David M
MTB衍生的抗原对人CD8+ T细胞的HLA-E依赖性表现。
影响因子：
15.3
作者：
Heinzel, Amy S;Grotzke, Jeff E;Lines, Rebecca A;Lewinsohn, Deborah A;McNabb, Andria L;Streblow, Daniel N;Braud, Veronique M;Grieser, Heather J;Belisle, John T;Lewinsohn, David M
通讯作者：
Lewinsohn, David M
影响因子：
4.5
作者：
Beatty, WL;Rhoades, ER;Russell, DG
通讯作者：
Russell, DG
影响因子：
20.3
作者：
Fonteneau, JF;Kavanagh, DG;Larsson, M
通讯作者：
Larsson, M
影响因子：
56.9
作者：
KOVACSOVICSBANKOWSKI, M;ROCK, KL
通讯作者：
ROCK, KL