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理解免疫系统如何控制病毒感染以及导致免疫介导的病理。我们在小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，这表明在抗原识别和适应新的记忆T细胞群的能力方面是可塑性的。作为一种感染的结果而形成的记忆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细胞依赖的异种免疫和免疫病理学。这笔赠款的重点是更好地了解与诱导异种免疫相关的机制，特别是交叉反应记忆T细胞反应和细胞因子在减少或增强病毒复制和改变免疫病理中所起的作用。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。这项建议将使用几种病毒，但继续关注淋巴细胞性脊膜炎(LCMV)和Pichinde(PV)病毒，这两种远亲病毒的T细胞反应被很好地定义，以及痘病毒痘苗(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，我们将能够对交叉反应性T反应在一系列病毒感染期间的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NP205的反应是否影响免疫优势等级、TCR使用和疾病结局。特定目标#2.测试LCMV、PV和W之间的交叉反应记忆性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.研究流感免疫小鼠LCMV或MCMV感染过程中病毒复制和免疫病理增强的机制。明确目标4：明确细胞因子在调节异种免疫中的作用。

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.