T Cell- Mediated Immunity to Mycobacterial Infection

描述（由申请人提供）：小鼠细胞内病原体如牛痘病毒(W)和单核增生李斯特菌（LM）的急性感染导致有效的T细胞反应，快速清除病原体，并建立长期记忆。相比之下，牛分枝杆菌卡介苗（BCG）在面对可检测到的CD4和CD8 T细胞应答时仍然存在，但对其相对大小、持续时间和产生记忆的能力知之甚少。研究LM和W的一个关键进展是产生表达模型抗原的重组病原体，如鸡卵白蛋白（OVA）。结合使用TCR转基因T细胞特异性的一类和二类限制性卵细胞表位，这些重组有助于促进体内对急性感染的免疫反应的表征。我们建议：1)通过创建重组BCG-OVA，使该技术用于表征抗分枝杆菌T细胞反应；2)剖析T细胞在对慢性感染的细胞内病原体（如卡介苗）和急性感染的病原体（如LM和W）产生灭菌、保护性免疫的能力方面的潜在差异；3)评估感染后分枝杆菌特异性记忆CD4和/或CD8 T细胞的激活、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有助于深入了解体内产生最佳CD4和CD8 T细胞反应的机制。

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.