T Cell- Mediated Immunity to Mycobacterial Infection

描述（由申请方提供）：用细胞内病原体如牛痘病毒（W）和单核细胞增生李斯特菌（LM）急性感染小鼠，导致有效的T细胞应答、病原体的快速清除和长期记忆的建立。相比之下，牛分枝杆菌卡介苗（BCG）在可检测到的CD 4和CD 8 T细胞反应面前仍然存在，但对它们的相对大小，持续时间和产生记忆的能力知之甚少。LM和W研究的一个关键进展是产生了表达模型抗原如鸡卵清蛋白（OVA）的重组病原体。结合使用TCR转基因T细胞的I类和II类限制性的OVA表位，这些重组体有助于促进急性感染的体内免疫应答的表征。我们建议：1）通过产生BCG-OVA重组体使该技术适于表征抗分枝杆菌T细胞应答; 2）剖析T细胞应答在它们对慢性感染的细胞内病原体如BCG和急性感染的病原体如LM和W产生杀菌、保护性免疫的能力方面的潜在差异;和3）评估感染后分枝杆菌特异性记忆CD 4和/或CD 8 T细胞的活化、扩增和保护能力。增强对这些感染的免疫反应如何不同的理解将提供对体内产生最佳CD 4和CD 8 T细胞反应的机制的深入了解。

DESCRIPTION(provided by the applicant): Acute infection of mice with intracellular pathogens such as Vaccinia virus (W) and Listeria monocytogenes (LM) results in potent T cell responses, rapid clearance of the pathogen, and the establishment of long-lived memory. In contrast, Mycobacterium bovis bacillus Calmette-Guerin (BCG) persists in the face of detectable CD4 and CD8 T cell responses, with much less known about their relative size, duration, and ability to generate memory. A key advance in the study of LM and W has been the generation of recombinant pathogens expressing model antigens such as chicken ovalbumin (OVA). Combined with the use of TCR transgenic T cells specific for Class I- and Class II-restricted OVA epitopes, these recombinants have helped facilitate the characterization of in vivo immune responses to acute infection. We propose to: 1) adapt this technology to characterize anti-mycobacterial T cell responses by the creation of a BCG-OVA recombinant; 2) dissect underlying differences of T cell responses in their ability to generate sterilizing, protective immunity to chronically infecting intracellular pathogens such as BCG and acutely infecting pathogens such as LM and W; and 3) assess the activation, expansion, and protective capacity of mycobacteria-specific memory CD4 and/or CD8 T cells following infection. An enhanced understanding of how immune responses to these infections differ will provide insight into the mechanisms governing the generation of optimal CD4 and CD8 T cell responses in vivo.