ESAT-6-specific CD4 T cell responses to aerosol Mycobacterium tuberculosis infection are initiated in the mediastinal lymph nodes
ESAT-6-specific CD4 T cell responses to aerosol Mycobacterium tuberculosis infection are initiated in the mediastinal lymph nodes
复制标题
DOI：
10.1073/pnas.0801496105
复制
发表时间：
2008-08-05
影响因子：
11.1
通讯作者：
Woodland, David L.
中科院分区：
文献类型：
--
作者：
Reiley, William W.;Calayag, Mark D.;Woodland, David L.
对气溶胶结核分枝杆菌（Mtb）感染的CD 4（+）T细胞应答的特征在于效应T细胞在肺中的相对延迟出现。这种适应性反应的延迟可能是允许细菌建立持续感染的关键。由于与幼稚T细胞的低频率的检测相关的限制，不可能精确地确定幼稚抗原特异性T细胞何时和何处被首次激活。我们已经解决了这个问题，通过使用早期分泌的抗原靶6（ESAT-6）特异性转基因CD 4 T细胞，以监测早期T细胞体内活化。通过使用过继转移方法，我们直接表明T细胞对ESAT-6的致敏仅发生在感染10天后，最初仅限于纵膈淋巴结，并且不涉及其他淋巴结或肺部。致敏的CD 4 T细胞迅速分化成增殖效应细胞，并最终获得离体产生IFN-γ和TNF-α的能力。T细胞引发的启动增强了整整两天，这取决于挑战接种物的大小，这表明抗原可用性是限制早期CD 4 T细胞应答的一个因素。这些数据定义了对Mtb感染的适应性免疫应答中的关键时期。
CD4(+) T cell responses to aerosol Mycobacterium tuberculosis (Mtb) infection are characterized by the relatively delayed appearance of effector T cells in the lungs. This delay in the adaptive response is likely critical in allowing the bacteria to establish persistent infection. Because of limitations associated with the detection of low frequencies of naive T cells, it had not been possible to precisely determine when and where naive antigen-specific T cells are first activated. We have addressed this problem by using early secreted antigenic target 6 (ESAT-6)-specific transgenic CD4 T cells to monitor early T cell activation in vivo. By using an adoptive transfer approach, we directly show that T cell priming to ESAT-6 occurs only after 10 days of infection, is initially restricted to the mediastinal lymph nodes, and does not involve other lymph nodes or the lungs. Primed CD4 T cells rapidly differentiated into proliferating effector cells and ultimately acquired the ability to produce IFN-gamma and TNF-alpha ex vivo. Initiation of T cell priming was enhanced by two full days depending on the magnitude of the challenge inoculum, which suggests that antigen availability is a factor limiting the early CD4 T cell response. These data define a key period in the adaptive immune response to Mtb infection.