Regulation of CD8 T cell memory by autocrine IL-2

自分泌 IL-2 对 CD8 T 细胞记忆的调节

• 批准号: 8893289
• 负责人: Vandana Kalia
• 金额: $ 7.54万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893289
• 关键词: Acids; Acute; Adoptive Transfer; Affinity; Antigens; Belief; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Communicable Diseases; Communities; Data; Defect; Defense Mechanisms; Dendritic Cells; Development; Economics; Effector Cell; Environment; Equilibrium; Exertion; Exhibits; Funding Mechanisms; Future; Goals; Growth Factor; HIV; Hematopoietic; Hepatitis C virus; Immune; Immunity; Immunization; Immunologic Memory; Immunotherapeutic agent; Infection; Interleukin-2; Investigation; Knock-out; Knockout Mice; Knowledge; Life; Longitudinal Studies; Malaria; Memory; Modeling; Molecular; Mus; Natural Killer Cells; Phase; Physiological; Production; Property; Regulation; Regulator Genes; Relative (related person); Research; Research Project Grants; Resources; Role; Secondary to; Signal Transduction; Source; Staging; Supplementation; T cell response; T memory cell; T-Lymphocyte; Testing; Time; Transgenic Mice; Tuberculosis; Ursidae Family; Vaccines; Viral; Virus Diseases; autocrine; base; biological systems; cell growth; cytokine; design; frontier; global health; imprint; improved; in vivo; insight; novel; paracrine; pathogen; programs; public health relevance; receptor; response; tumor

 DESCRIPTION (provided by applicant): Interleukin-2 (IL-2), originally identified as a T-cell growth factor, is possibly the most studied cytokine, yet newer physiologic functions continue to be ascribed to it. In addition to its pivotal role in regulating tolerance, IL-2 signals are criticl for generating functional CD8 T cell memory to pathogens. We recently demonstrated a critical role of IL-2 in balancing effector and memory responses during acute viral infections. Moreover, contrary to common belief that effector CD8 T cells do not produce IL-2, in a surprise finding we discovered that memory-fated effector cells produce large amounts of IL-2 and retain this ability throughout effector and memory stages. Indeed, robust IL-2 production is a hallmark property of long-lived polyfunctional memory cells and is required for robust secondary expansion. In one of the most stringent tests for physiological relevance of autocrine IL-2 signals, we adoptively transferred equal numbers of wild-type and IL-2-/- antigen-specific CD8 T cells into wild-type recipients, and followed memory differentiation within the same host in response to acute infection. Excitingly, we found that despite being in an environment where all other hematopoietic and nonhematopoietic cells and half of the antigen-specific CD8 T cells were capable of producing their own IL-2, IL-2-/- memory CD8 T cells were compromised in mounting robust secondary expansion upon rechallenge. This focused R03 proposal seeks to further extend these promising preliminary observations towards gaining insight into when autocrine IL-2 signals regulate cardinal CD8 T cell memory property of secondary expansion, and how paracrine IL-2 sources participate. Using novel conditional IL-2 knockout mice, we will extinguish autocrine or paracrine IL-2 signals either during primary CD8 T cell expansion (when memory properties are imprinted), or during secondary expansion phases (when memory cells undergo rapid proliferative burst and effector differentiation) to explore the timing of action of L-2 signals. We will employ phenotypic, functional and transcriptional profiling studies to gain molecular insight into how IL-2 signals regulate CTL immunity. For development of efficacious vaccines and immunization strategies that induce protective, long-lived CD8 T cell immunological memory, it is important to know why memory CD8 T cells produce their own IL-2, when and how this regulates memory properties and whether IL-2 signals can be provided in trans for optimal memory responses. Moreover, these studies lay the developmental groundwork for a future R01 proposal - narrowing down the time frame of action of autocrine IL-2 signals and a clear identification of the broad cellular and molecular networks involved will help us appropriately focus our future mechanistic investigations of autocrine IL-2 regulated gene regulatory networks under the auspice of a R01 funding mechanism.

 描述（由申请人提供）：白细胞介素-2（IL-2），最初被鉴定为T细胞生长因子，可能是研究最多的细胞因子，然而更新的生理功能继续归因于它。我们最近证明了IL-2在急性病毒感染期间平衡效应器和记忆反应中的关键作用。此外，与效应CD 8 T细胞不产生IL-2的普遍看法相反，我们意外地发现记忆命运效应细胞产生大量IL-2，并在整个效应和记忆阶段保持这种能力。事实上，稳健的IL-2产生是长寿命多功能记忆细胞的标志性特性，并且是稳健的二次扩增所需的。 在对自分泌IL-2信号的生理相关性的最严格的测试中，我们将相同数量的野生型和IL-2-/-抗原特异性CD 8 T细胞过继转移到野生型受体中，并在同一宿主内响应于急性感染进行记忆分化。令人兴奋的是，我们发现，尽管处于所有其他造血细胞和非造血细胞以及一半抗原特异性CD 8 T细胞能够产生其自身IL-2的环境中，但IL-2-/-记忆CD 8 T细胞在再激发后的稳健二次扩增中受到损害。这一集中的R 03提案旨在进一步扩展这些有希望的初步观察，以深入了解自分泌IL-2信号何时调节次级扩增的主要CD 8 T细胞记忆特性，以及旁分泌IL-2来源如何参与。使用新的条件性IL-2敲除小鼠，我们将在初级CD 8 T细胞扩增期间（当记忆特性被印记时）或在次级扩增阶段期间（当记忆细胞经历快速增殖爆发和效应分化时）消除自分泌或旁分泌IL-2信号，以探索L-2信号的作用时间。我们将采用表型，功能和转录谱研究，以获得分子洞察IL-2信号如何调节CTL免疫。 为了开发诱导保护性、长寿的CD 8 T细胞免疫记忆的有效疫苗和免疫策略，重要的是要知道为什么记忆性CD 8 T细胞产生它们自己的IL-2，何时以及如何调节记忆特性，以及IL-2信号是否可以反式提供以获得最佳记忆应答。此外，这些研究为未来的R 01提案奠定了发展基础-缩小自分泌IL-2信号作用的时间框架，并明确识别所涉及的广泛的细胞和分子网络，将有助于我们在R 01资助机制的支持下，适当地集中于自分泌IL-2调节基因调控网络的未来机制研究。