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Regulation of mucosal memory CD8 T cells by Thymic Stromal Lymphopoietin

胸腺基质淋巴细胞生成素对粘膜记忆 CD8 T 细胞的调节

基本信息

批准号：
7706298
负责人：
Kimberly D. Klonowski
金额：
$ 18.55万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-22 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7706298
关键词：
Adoptive Transfer Affect Animals Anti-Bacterial Agents Antigens Binding Biological CD4 Positive T Lymphocytes CD8B1 gene Cell Lineage Cells Cellular biology Dendritic Cells Development Ensure Enteral Epithelial Cells Equilibrium Frequencies Gastrointestinal tract structure Generations Genetically Modified Animals Goals Homeostasis Immune Immune response Immunologic Memory Immunotherapy In Situ In Vitro Infection Interleukin-15 Interleukin-7 Intestines Kinetics Left Listeria monocytogenes Maintenance Memory Mucous Membrane Oral Participant Phase Phenotype Play Population Positioning Attribute Property Regulation Role Shapes Signal Transduction Small Intestines Staging Surface System T memory cell T-Cell Development T-Lymphocyte Transgenic Animals Transgenic Organisms Vaccines conditioning cytokine design efficacy research enteric pathogen human TSLP protein improved migration novel therapeutic intervention oral pathogen overexpression pathogen precursor cell receptor receptor expression research study response self-renewal

项目摘要

DESCRIPTION (provided by applicant): Thymic Stromal Lymphopoietin (TSLP) is a recently described cytokine which shares a receptor component (IL-7Ra) and significant biological redundancy with Interleukin-7. TSLP is predominately expressed by mucosal epithelial cells, which positions TSLP to play a role in orchestrating immune responses during infection with oral pathogens, including L. monocytogenes. Receptors for TSLP are not only expressed by CD8 T cells but also by dendritic cells which actively participate in shaping the generation of CD8 T cell memory. The goal of this proposal is to understand how TSLP both directly and indirectly affects the formation and maintenance of CD8 T cell memory. In Aim 1 we will study the kinetics of TSLP expression during oral L. monocytogenes infection and examine TSLP receptor expression on anti-bacterial CD8 T cells. We will use transgenic animals to modulate either TSLP or TSLP receptor expression to determine how the cytokine directly interacts with and impacts the fate of mucosal memory CD8 T cells. In Aim 2 we will use both in vitro culture systems and genetically modified animals to determine how populations of TSLP-conditioned DCs affect CD8 T cell priming, memory development, and homeostasis during enteric infection. Together, these studies will provide a global view of how TSLP regulates multiple lineages of cells which play active roles in CD8 T cell biology and will further our understanding of mucosal memory CD8 T cell development. This in turn will help in designing novel therapeutic interventions and vaccines, particularly those aimed at boosting immune responses at mucosal surfaces.

描述（由申请人提供）：胸腺基质淋巴细胞生成素（TSLP）是最近描述的一种细胞因子，其与白细胞介素7共享受体成分（IL-7Ra）并具有显着的生物学冗余。 TSLP 主要由粘膜上皮细胞表达，这使得 TSLP 在口腔病原体（包括单核细胞增生李斯特菌）感染期间在协调免疫反应中发挥作用。 TSLP 受体不仅由 CD8 T 细胞表达，还由积极参与形成 CD8 T 细胞记忆生成的树突状细胞表达。该提案的目标是了解 TSLP 如何直接和间接影响 CD8 T 细胞记忆的形成和维持。在目标 1 中，我们将研究口腔单核细胞增生李斯特菌感染期间 TSLP 表达的动力学，并检查抗菌 CD8 T 细胞上的 TSLP 受体表达。我们将使用转基因动物来调节 TSLP 或 TSLP 受体表达，以确定细胞因子如何直接与粘膜记忆 CD8 T 细胞相互作用并影响其命运。在目标 2 中，我们将使用体外培养系统和转基因动物来确定 TSLP 条件化 DC 群体如何影响肠道感染期间 CD8 T 细胞启动、记忆发育和体内平衡。总之，这些研究将提供 TSLP 如何调节在 CD8 T 细胞生物学中发挥积极作用的多种细胞谱系的全局视角，并将进一步加深我们对粘膜记忆 CD8 T 细胞发育的理解。这反过来将有助于设计新的治疗干预措施和疫苗，特别是那些旨在增强粘膜表面免疫反应的干预措施和疫苗。