Virus Induced Immunopathology

描述(由申请人提供)：理解免疫系统如何控制病毒感染、病毒感染如何改变免疫系统功能以及如何设计有效、持久的疫苗，需要了解与诱导和保存免疫记忆相关的机制。我们在小鼠系统中对病毒的研究表明，CD8 T细胞的记忆通常是稳定的，但这种稳定性会被其他病原体破坏，这些病原体的感染会导致记忆丧失。叠加在这个过程上的是T细胞识别的退化，这使得T细胞经常在无关的病毒之间发生交叉反应，从而导致记忆池中交叉反应的T细胞丰富。作为一次感染的结果，记忆T细胞可以影响保护性免疫和与第二次感染无关病毒相关的免疫病理学，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。 我们定义了新的模型系统，并组装了合适的试剂和分子技术，以深入描述一系列病毒感染期间交叉反应和非交叉反应CD8T细胞反应的演变，并对CD8T细胞群体的一般生活、死亡和亲和力成熟做出独特的见解。这项建议使用了几种病毒，但重点是淋巴细胞性脉络膜脑炎(LCMV)和Pichinde(PV)病毒，T细胞反应非常明确的旧世界和新世界Arena病毒，以及被用作天花疫苗和许多其他抗原的重组疫苗和载体的痘苗病毒(VV)。我们建议在支持以下特定目标的工作中探索CD8 T细胞反应的演变： 具体目的1.确定在连续感染编码交叉反应表位的急性和持久性病毒期间T细胞谱系如何演变。 特异性目的2：确定在缺乏外来抗原信号的情况下，哪些T细胞功能发生。 目的：解决VV感染所致记忆T细胞增殖的复杂模式。 LCMV免疫小鼠，作为异种免疫模型。 特定目的#4.确定在淋巴细胞减少环境的动态平衡重建中病毒特异性T细胞不足的基础。

DESCRIPTION (provided by applicant): Understanding the mechanisms associated with the induction and preservation of immunological memory is needed for the comprehension of how the immune system controls viral infections, how viral infections alter immune system function, and how effective, long-lasting vaccines can best be designed. Our studies with viruses in murine systems have shown that CD8 T cell memory is normally stable, but that this stability is disrupted by other pathogens, whose infections contribute to a loss in memory. Superimposed on this process is the degeneracy of T cell recognition, which allows T cells to often cross-react between unrelated viruses, thereby resulting in an enrichment in cross-reactive T cells in the memory pool. Memory T cells laid down as a consequence of one infection can influence protective immunity and immunopathology associated with a second infection with an unrelated virus, and we have referred to this phenomenon as T cell-dependent heterologous immunity and immunopathology. We have defined new model systems and assembled suitable reagents and molecular techniques to perform an in depth characterization of the evolution of cross-reactive and non-cross-reactive CD8 T cell responses during a series of viral infections and to make unique insights into the life, death, and affinity maturation of CD8 T cell populations in general. This proposal uses several viruses but focuses on lymphocytic choriomenigitis (LCMV) and Pichinde (PV) viruses, Old World and New World arenaviruses whose T cell responses are very well-defined, and on the poxvirus vaccinia (VV), which is used as a vaccine for small pox and as a recombinant vaccine and vector for many other antigens. We propose to explore the evolution of CD8 T cell responses in work supporting the following specific aims: SPECIFIC AIM #1. To determine how the T cell repertoire evolves during sequential infections with acute and persistent viruses encoding cross-reactive epitopes. SPECIFIC AIM #2. To determine which T cell functions occur in the absence of foreign antigen signaling. SPECIFIC AIM #3. To resolve the complex patterns of memory T cell proliferation induced by VV-infection of LCMV-immune mice, as a model for heterologous immunity. SPECIFIC AIM #4. To determine the basis for the deficiency of virus-specific T cells in the homeostatic reconstitution of lymphopenic environments.