Immunity in systemic and mucosal virus infections

描述（由申请人提供）：全面了解与免疫T细胞记忆的产生和调节相关的机制，将有助于更好地了解免疫系统如何控制病毒感染，以及如何引起免疫介导的病理学。我们在鼠系统中对病毒的研究集中在病毒特异性记忆T细胞群上，这些细胞群在抗原识别和适应新的记忆T细胞群的能力方面表现出可塑性。作为一种感染的结果，记忆T细胞可以影响与第二种无关病毒相关的保护性免疫和免疫病理学。我们将这种现象称为T细胞依赖性异源免疫和免疫病理学。这项资助的重点是更好地理解与诱导异源免疫相关的机制，特别是交叉反应性记忆T细胞应答和细胞因子在减少或增加病毒复制和改变免疫病理学中的作用。我们已经确定了病毒之间潜在的交叉反应表位，开发了全身和呼吸道感染模型系统，并组装了合适的试剂和分子技术。该提案将使用几种病毒，但继续关注淋巴细胞性脑膜炎（LCMV）和皮钦德（PV）病毒，它们是T细胞反应明确的远亲沙粒病毒，以及痘病毒牛痘（W），它被用作天花疫苗和许多抗原的重组疫苗和载体。有了这些基线信息和技术，我们将能够对一系列病毒感染期间交叉反应性T细胞应答在异源免疫中所起的作用进行深入分析。具体目标#1。测试CDS T细胞对LCMV和PV之间几乎相同的交叉反应表位NP 205的应答是否影响免疫优势等级、TCR使用和疾病结果。具体目标#2测试LCMV、PV和W之间的交叉反应性记忆CDS T细胞矩阵是否影响免疫优势等级、TCR使用和疾病结局。具体目标#3检查流感免疫小鼠LCMV或MCMV感染期间病毒复制增强和免疫病理学的机制。具体目标#4明确细胞因子在介导异源免疫中的作用。

DESCRIPTION (provided by applicant): A comprehensive understanding of the mechanisms associated with the generation and modulation of immunological T cell memory will lead to a better understanding of not only how the immune system controls viral infections but also causes immune-mediated pathology. Our studies with viruses in murine systems have focused on virus-specific memory T cell populations, which demonstrate plasticity in antigen recognition and in their ability to accommodate new memory T cell populations. Memory T cells laid down as a consequence of one infection can influence protective immunity and immunopathology associated with a second unrelated virus. We have referred to this phenomenon as T cell-dependent heterologous immunity and immunopathology. The focus of this grant is to develop a better understanding of the mechanisms associated with the induction of heterologous immunity, specifically the role cross-reactive memory T cell responses and cytokines play in decreasing or augmenting viral replication and altering immunopathology. We have identified potential cross-reactive epitopes between viruses, developed both systemic and respiratory infection model systems, and assembled suitable reagents and molecular techniques. This proposal will use several viruses, but continues to focus on lymphocytic chorimeningitis (LCMV) and Pichinde (PV) viruses, distantly related arenaviruses whose T cell responses are well defined, and on the poxvirus vaccinia (W), which is used as a vaccine for smallpox and as a recombinant vaccine and vector for many antigens. With this baseline information and techniques we will be able to perform an in depth analysis of the role that cross-reactive T responses play in heterologous immunity during a series of viral infections. Specific Aim #1. Test whether CDS T cell responses to the nearly identical cross-reactive epitope, NP205, between LCMV and PV influence immunodominance hierarchy, TCR usage, and disease outcome. Specific Aim #2. Test whether a matrix of cross-reactive memory CDS T cells between LCMV, PV and W influence immunodominance hierarchy, TCR usage, and disease outcome. Specific Aim #3. Examine the mechanisms involved in augmented viral replication and immunopathology during LCMV or MCMV infection of influenza-immune mice. Specific Aim #4. Define the role of cytokines in mediating heterologous immunity.