Virus Induced Immunopathology

描述（由申请人提供）：了解与免疫记忆的诱导和保存相关的机制是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、持久的疫苗所必需的。我们对小鼠系统中病毒的研究表明，CD8 T细胞的记忆通常是稳定的，但这种稳定性被其他病原体破坏，这些病原体的感染导致记忆丧失。叠加在这个过程上的是T细胞识别的退化，这使得T细胞经常在不相关的病毒之间交叉反应，从而导致记忆池中交叉反应的T细胞的富集。由于一次感染而产生的记忆T细胞可以影响与第二次感染无关病毒相关的保护性免疫和免疫病理，我们将这种现象称为T细胞依赖性异源免疫和免疫病理。

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.