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

人口贩卖

• 批准号: 8740675
• 负责人: Jason M Schenkel
• 金额: $ 2.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8740675
• 关键词: Adoptive Transfer; CC chemokine receptor 7; CCL19 gene; CCL21 gene; CCR9 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Cessation of life; Characteristics; Classification; Data; Enteral; Flow Cytometry; Generations; Heterogeneity; Home environment; Hospitalization; Immune response; Immunobiology; Immunofluorescence Microscopy; Infection; Inflammation; Knowledge; Listeria monocytogenes; Lymph; Lymphatic; Lymphoid; Lymphoid Tissue; Memory; Mesentery; Mind; Mission; National Institute of Diabetes and Digestive and Kidney Diseases; Natural Killer Cells; Organ; Pattern; Phenotype; Population; Reporting; Role; SELL gene; Selectins; Site; Small Intestines; Stable Populations; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Tissues; Vaccine Design; Viral; Viral Gastroenteritis; base; cell motility; chemokine receptor; cytokine; cytotoxic; gastrointestinal infection; in vivo; lymph nodes; novel; pathogen; public health relevance; receptor; response; terminally differentiated effector memory (TEM) T cells; therapeutic vaccine; trafficking; vaccine development

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.

描述（由申请人提供）：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。CD 8 T细胞是控制细胞内感染的有效细胞毒性细胞，因此，代表了治疗和疫苗开发的潜在目标群体。考虑到这一点，相当多的表征，包括CD 8 T细胞免疫生物学的许多方面，导致我们对CD 8 T细胞功能的一般理解大幅增加。直到最近，病原体攻击后记忆性CD 8 T细胞功能的范例集中在记忆性CD 8 T细胞应答主要在次级淋巴组织内产生的假设上。然而，新的报告强调了记忆性CD 8 T细胞在次级淋巴组织外的重要功能。例如，最近已经表明，非淋巴组织内的记忆性CD 8 T细胞提供了对局部病原体攻击的重要和有效的早期应答。这种情况发生的机制仍然不完全清楚，也不知道这些反应如何与感染组织外的CD 8 T细胞产生的反应相关。展望未来，关键是要了解感染组织内的这些反应是否与感染部位外的CD 8 T细胞以合作或平行方式运作。该提议的中心假设是在组织外存在多个记忆性CD 8 T细胞群体，其在稳态条件下和炎症状态期间差异性地迁移到小肠中。此外，这些记忆性CD 8 T细胞可能在小肠内提供重要的早期细胞毒性反应波。因此，我的具体目标将是1）确定这些不同群体应对病原体挑战的功能和重要性; 2）确定这些不同CD 8 T细胞记忆群体的稳定性和运输模式。该建议支持NIDDK的使命，因为它专注于了解记忆CD 8 T细胞对细胞内胃肠道感染的反应。随着对小肠记忆性CD 8 T细胞功能的进一步了解，可以为合理设计靶向CD 8 T细胞的疫苗提供重要信息。