Trafficking & role of effector memory CD8T cell subsets in small intestine

描述(申请人提供)：细胞内肠道感染是一个全球性问题，每年导致数百万人住院和死亡。CD8T细胞是控制细胞内感染的强有力的细胞毒细胞，因此是治疗和疫苗开发的潜在靶点。考虑到这一点，相当多的特征，包括CD8T细胞免疫生物学的许多方面，导致我们对CD8T细胞功能的总体理解有了实质性的增加。直到最近，关于记忆CD8 T细胞在病原体攻击时的功能的范例都集中在一个假设上，即记忆CD8 T细胞反应主要发生在次级淋巴组织中。然而，更新的报道强调了次级淋巴组织外记忆CD8 T细胞的重要功能。例如，最近的研究表明，非淋巴组织中的记忆CD8T细胞对局部病原体的攻击提供了重要而有力的早期反应。发生这种情况的机制仍不完全清楚，也不知道这些反应与感染组织外的CD8 T细胞产生的反应如何相关。接下来，了解感染组织内的这些反应是否与感染部位外的CD8 T细胞以协同或并行的方式运作将是至关重要的。这一建议的中心假设是，在组织外存在多种记忆性CD8 T细胞，在体内平衡条件下和在炎症状态下，这些细胞差异地迁移到小肠中。此外，这些记忆CD8 T细胞可能在小肠内提供重要的早期细胞毒反应波。因此，我的特定目标将1)确定这些不同群体在应对病原体挑战时的功能和重要性；2)确定这些不同群体CD8 T细胞记忆的稳定性和运输模式。这项建议支持NIDDK的使命，因为它侧重于了解记忆CD8 T细胞对细胞内胃肠道感染的反应。通过对小肠记忆性CD8 T细胞功能的深入了解，可以为合理设计针对CD8 T细胞的疫苗提供重要信息。

DESCRIPTION (provided by applicant): Intracellular enteric infections are a global problem resulting in millions of hospitalizations and deaths every year. CD8 T cells are potent cytotoxic cells that control intracellular infection, and as such, represent a potential population to targetfor therapeutics and vaccine development. With this in mind, considerable characterizations, encompassing many aspects of CD8 T cell immunobiology, have resulted in substantial increases in our general understanding of CD8 T cell function. Up until recently, the paradigm for memory CD8 T cell function upon pathogen challenge centered on the hypothesis that memory CD8 T cell responses were predominantly generated within secondary lymphoid tissue. However, newer reports have highlighted important functions of memory CD8 T cells outside of secondary lymphoid tissue. For instance, it has recently been shown that memory CD8 T cells within nonlymphoid tissues provide important and potent early responses to local pathogen challenge. The mechanism by which this occurs is still not entirely understood, nor is it known how these responses are related to ones generated by CD8 T cells outside of the infected tissue. Moving forward, it will be critical to understand whether these responses within infected tissues operate in cooperative versus parallel manners with CD8 T cells outside of the infected site. The central hypothesis of this proposal is that there exist multiple populations of memory CD8 T cells outside of tissues that differentially migrate into the small intestine under homeostatic conditions and during states of inflammation. Further, these memory CD8 T cells may provide an important, early wave of cytotoxic responses within the small intestine. Therefore, my specific aims will 1) determine the functionality and importance of these different populations in response to pathogen challenge; 2) determine the stability and trafficking patterns of these different populations of CD8 T cell memory. This proposal supports the mission of the NIDDK because it focuses understanding memory CD8 T cell responses to intracellular gastrointestinal infections. With a better understanding of memory CD8 T cell function in the small intestine, could provide important information for rational vaccine design targeting CD8 T cells.