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Cytokine regulation of memory CD8 T cell responses

记忆 CD8 T 细胞反应的细胞因子调节

基本信息

批准号：
8490285
负责人：
Kimberly D. Klonowski
金额：
$ 27.36万
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：
2009-07-25 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8490285
关键词：
Adoptive Transfer Affect Allergic Animals Antigens Atopic Dermatitis Binding Biological CD4 Positive T Lymphocytes CD8B1 gene Cell Differentiation process Cell Lineage Cells Cellular biology Dendritic Cells Development Ensure Epithelial Cells Extrinsic asthma Frequencies Generations Genetically Modified Animals Goals Homeostasis Immune Immune response Immunologic Memory Immunotherapy In Vitro Infection Influenza Interleukin-15 Interleukin-7 Kinetics Left Lung Maintenance Memory Participant Phase Phenotype Play Population Positioning Attribute Production Property Regulation Research Respiratory System Respiratory tract structure Role Shapes Signal Transduction Site Staging Surface System T cell response T memory cell T-Cell Development T-Lymphocyte Th2 Cells Tissues Transgenic Animals Transgenic Organisms Vaccines Viral Virus Virus Diseases base conditioning cytokine design human TSLP protein improved influenzavirus migration novel therapeutic intervention overexpression pathogen precursor cell public health relevance receptor receptor expression research study response self-renewal therapeutic vaccine

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 influenza A, which targets epithelial cells in the lungs. Receptors for TSLP are not only expressed by CD8 T cells but also dendritic cells and CD4 T 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 during influenza virus infection and examine TSLP receptor expression on anti-viral 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 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. In Aim 3 we will perform adoptive transfers to determine how TSLP influences the type and quality of help CD4 T cells provide to CD8 T cells and how these alterations affect memory development and the maintenance of tissue-specific memory CD8 T cells. 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 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 在甲型流感感染期间在协调免疫反应中发挥作用，甲型流感以肺部上皮细胞为目标。 TSLP 受体不仅由 CD8 T 细胞表达，还由树突状细胞和 CD4 T 细胞表达，它们积极参与塑造 CD8 T 细胞记忆的生成。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，我们将研究流感病毒感染期间 TSLP 的动力学，并检查抗病毒 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 CD8 T 细胞启动、记忆发育和体内平衡。在目标 3 中，我们将进行过继转移，以确定 TSLP 如何影响 CD4 T 细胞向 CD8 T 细胞提供帮助的类型和质量，以及这些改变如何影响记忆发育和组织特异性记忆 CD8 T 细胞的维持。总之，这些研究将为 TSLP 如何调节在 CD8 T 细胞生物学中发挥积极作用的多个细胞谱系提供全局视角，并将进一步加深我们对记忆 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。