Cytokine regulation of memory CD8 T cell responses

记忆 CD8 T 细胞反应的细胞因子调节

• 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
• 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

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。公共卫生相关性：免疫记忆是成功疫苗的基础，因为它确保在二次接触后快速清除相同的病原体。该提案的目标是确定特定分子胸腺基质淋巴细胞生成素 (TSLP) 如何影响记忆细胞的生成和长期存活。了解和利用调节记忆的因素对于开发具有更高功效的疫苗至关重要。