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: 7631749
• 负责人: Kimberly D. Klonowski
• 金额: $ 29.7万
• 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/7631749
• 关键词: Adoptive Transfer; Affect; Allergic; Animals; Antigens; Asthma; Atopic Dermatitis; Binding; Biological; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Differentiation process; Cell Lineage; Cells; Cellular biology; Dendritic Cells; Development; Ensure; Epithelial Cells; Frequencies; Generations; Genetically Modified Animals; Goals; Homeostasis; Immune; Immune response; Immunologic Memory; Immunotherapy; In Vitro; Infection; Influenza; Interleukin-15; Interleukin-7; Kinetics; Left; Lung; Lymphoid; Maintenance; Memory; Participant; Phase; Phenotype; Play; Population; Positioning Attribute; Production; Property; Regulation; Respiratory System; Respiratory tract structure; Role; Shapes; Signal Transduction; Site; Staging; Surface; System; T memory cell; T-Cell Development; T-Lymphocyte; Th2 Cells; Tissues; Transgenic Animals; Transgenic Organisms; Vaccines; Viral; Virus; Virus Diseases; base; conditioning; cytokine; design; efficacy research; human TSLP protein; improved; influenzavirus; migration; novel therapeutic intervention; overexpression; pathogen; precursor cell; public health relevance; receptor; receptor expression; research study; response; self-renewal

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）：胸腺基质促红细胞生成素（TSLP）是最近描述的细胞因子，其与白细胞介素-7共享受体组分（IL-7 Ra）和显著的生物学冗余。TSLP主要由粘膜上皮细胞表达，其使TSLP在甲型流感感染期间在协调免疫应答中发挥作用，甲型流感靶向肺中的上皮细胞。TSLP受体不仅由CD 8 T细胞表达，而且由树突状细胞和CD 4 T细胞表达，其积极参与形成CD 8 T细胞记忆的产生。本提案的目标是了解TSLP如何直接和间接影响CD 8 T细胞记忆的形成和维持。在目的1中，我们将研究流感病毒感染期间TSLP的动力学，并检测抗病毒CD 8 T细胞上TSLP受体的表达。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性CD 8 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DC群体如何影响CD 8 T细胞启动、记忆发育和稳态。在目标3中，我们将进行过继转移，以确定TSLP如何影响CD 4 T细胞向CD 8 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CD 8 T细胞的维持。总之，这些研究将提供TSLP如何调节在CD 8 T细胞生物学中发挥积极作用的多个细胞谱系的全局视图，并将进一步加深我们对记忆性CD 8 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，因为它确保在第二次遭遇后快速清除相同的病原体。这项计划的目的是确定一种特定的分子，胸腺基质细胞生成素（TSLP），如何影响记忆细胞的产生和长期存活。了解和利用调节记忆的因素对于开发具有改进功效的疫苗至关重要。