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：
8290480
负责人：
Kimberly D. Klonowski
金额：
$ 29.11万
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8290480
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. Public Health Relevance: Immunological memory is the basis of a successful vaccine as it ensures rapid clearance of the identical pathogen following a secondary encounter. The goal of this proposal is to determine how a specific molecule, Thymic Stromal Lymphopoietin (TSLP), influences both the generation and long-term survival of memory cells. Understanding and exploiting the factors regulating memory is paramount to developing vaccines with improved efficacy.

描述（由申请人提供）：胸腺基质淋巴细胞生成素（TSLP）是最近描述的细胞因子，它具有与interleukin-7共享受体成分（IL-7RA）和显着的生物学冗余。 TSLP主要由粘膜上皮细胞表达，该细胞将TSLP定位为在感染型流感型在感染过程中的免疫反应中发挥作用，该感染靶向肺部的上皮细胞。 TSLP的受体不仅由CD8 T细胞表达，还表达了树突状细胞和CD4 T细胞，这些细胞和CD4 T细胞积极参与塑造CD8 T细胞存储器的产生。该建议的目的是了解TSLP如何直接和间接影响CD8 T细胞存储器的形成和维护。在AIM 1中，我们将研究流感病毒感染过程中TSLP的动力学，并检查抗病毒CD8 T细胞上TSLP受体的表达。我们将使用转基因动物调节TSLP或TSLP受体表达，以确定细胞因子如何直接与记忆CD8 T细胞的命运直接相互作用并影响。在AIM 2中，我们将同时使用体外培养系统和转基因动物来确定TSLP条件的DC的种群如何影响CD8 T细胞启动，记忆发展和稳态。在AIM 3中，我们将进行收养转移，以确定TSLP如何影响CD4 T细胞为CD8 T细胞提供的帮助的类型和质量，以及这些改变如何影响记忆发展以及维持组织特异性记忆CD8 T细胞的维持。总之，这些研究将提供全球视图，即TSLP如何调节在CD8 T细胞生物学中起积极作用的细胞的多个谱系，并将进一步了解我们对记忆CD8 T细胞发育的理解。反过来，这将有助于设计新颖的治疗干预措施和疫苗，尤其是旨在增强粘膜表面免疫反应的疫苗。公共卫生相关性：免疫记忆是成功疫苗的基础，因为它可确保在第二次接触后快速清除相同的病原体。该建议的目的是确定特定的分子胸腺基质淋巴细胞增多素（TSLP）如何影响记忆细胞的产生和长期存活。理解和利用调节记忆的因素对于开发具有提高功效的疫苗至关重要。