Recognition of Mtb-infected cells by CD8+ T lymphocytes

描述(申请人提供)：结核病(TB)仍然是全球感染性死亡的主要原因。目前，唯一可用的结核病疫苗卡介苗(BCG)在预防成人结核病方面尚未被证明有效。因此，迫切需要一种改进的结核病疫苗。我们最近鉴定了人类结核分枝杆菌(Mtb)反应性CD8+T细胞，这些T细胞受非经典分子MR1的限制。该分子以前没有被证明呈现病原体相关的抗原。受MR1限制的T细胞通常使用一种特定的T细胞受体(TCR；V17.2)，这些细胞被称为粘膜相关不变T细胞(MAIT)。此外，我们还发现肺上皮细胞可以感染结核分枝杆菌，并能被CD8+T细胞有效识别。这项建议的具体目的是加强对呼吸道在控制结核分枝杆菌感染中所起作用的理解。我们最近发现，MR1限制性MAIT能够识别结核分枝杆菌和其他多种病原体，这些细胞和其他CD8+T细胞能够有效识别结核分枝杆菌感染的上皮细胞。目前，呼吸道上皮细胞在宿主对结核分枝杆菌感染反应中的作用尚不清楚。在第一个目标中，MAIT识别的病原体的全谱将根据TCR的使用情况进行表征。我们推测，有限的TCR使用量将与病原体识别方面的有限多样性相关。第二个目标将确定结核分枝杆菌在上皮细胞中的细胞内位置，并将确定抗原处理和递送途径中的关键成分。在这里，我们假设免疫系统已经进化出机制来采样结核分枝杆菌的细胞内环境。最后，我们将讨论iNOS在直接控制结核分枝杆菌生长中的作用。在这里，我们假设iNOS在人类中的主要作用存在于肺上皮水平。

DESCRIPTION (provided by applicant): Tuberculosis (TB) remains a leading cause of infectious mortality worldwide. At present, the only available vaccine for TB, Bacillus Calmette-Guirin (BCG), has not proven effective in the prevention of adult tuberculosis. As a result, an improved vaccine for TB is urgently needed. We have recently identified and characterized human, Mycobacterium tuberculosis (Mtb)-reactive, CD8+ T cells restricted by the non-classical (HLA-Ib) molecule MR1. This molecule has not previously been shown to present pathogen associated antigens. T cells restricted by MR1 often use a specific T cell receptor (TCR; V17.2).These cells have been termed Mucosa Associated Invariant T Cells (MAIT). Furthermore, we have also found that lung epithelial cells can be infected with Mtb, and are efficiently recognized by CD8+ T cells. The specific aims of this proposal are focused on developing an improved understanding of the role that the airway plays in the control of infection with Mtb. We have recently found that MR1-restricted MAIT are capable of recognizing Mtb as well as a variety of other pathogens, and that these and other CD8+ T cells are capable of efficiently recognizing Mtb-infected epithelial cells. At present, the role of airway epithelium in the host response to infection with Mtb remains relatively unexplored. In the first aim the full spectrum of pathogens recognized by MAIT will be characterized with regard to TCR usage. We postulate that the limited TCR usage will correlate with limited diversity with regard to pathogen discrimination. The second Aim will define the intracellular location of Mtb in epithelial cells, and will define critical components in the antigen processing and presentation pathway. Here, we postulate that the immune system has evolved mechanisms to sample the intracellular environment of Mtb. Finally, we will address the role of iNOS in the direct control of Mtb growth. Here, we postulate that the major role of iNOS in humans resides at the level of the lung epithelium.