Signals Affecting Homestasis and Tolerance in Memory T Cells

影响记忆 T 细胞稳态和耐受性的信号

• 批准号: 8068688
• 负责人: JONATHAN S MALTZMAN
• 金额: $ 38.53万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8068688
• 关键词: Acute; Address; Affect; Alloantigen; Allografting; Antigens; Binding; CD44 gene; Cell Proliferation; Cell Transplantation; Cells; Chronic; Clinical; Clinical Medicine; Complement; Cytokine Receptors; Data; Defect; Event; Exposure to; Gene Deletion; Generations; Genetic; Goals; Homeostasis; Human; Hyaluronic Acid; Immune; Immune system; Immunity; Individual; Infection; Infectious Agent; LCP2 gene; Leukocytes; Life; Listeria monocytogenes; Lymphocyte; Lymphopenia; MAP Kinase Gene; Mediating; Memory; Modeling; Molecular; Murid herpesvirus 1; Mus; Nature; Organ; Outcome; PTEN gene; Pathway interactions; Peptide/MHC Complex; Phenotype; Phosphoproteins; Phosphoric Monoester Hydrolases; Process; Proto-Oncogene Proteins c-akt; Protocols documentation; Reagent; Receptor Signaling; Relative (related person); Resistance; Rodent Model; Signal Pathway; Signal Transduction; Signaling Molecule; Solid; Study models; T memory cell; T-Cell Receptor; T-Lymphocyte; Time; Translations; Transplantation; Transplantation Tolerance; Vertebrates; Viral; Virus; Virus Diseases; allograft rejection; base; cross reactivity; design; extracellular; fighting; in vivo; innovation; mutant; novel; pathogen; public health relevance; receptor; receptor-mediated signaling; recombinase; response; src Homology Region 2 Domain

DESCRIPTION (provided by applicant): While it is relatively easy to induce long-term tolerance in rodent models, translation of these protocols to higher vertebrates and clinical medicine has been difficult. Unlike mice, humans are constantly exposed to viral pathogens which induce transient lymphopenia and the generation of immune memory. A known barrier to transplant in humans is a large number of alloreactive memory T cells, even in those individuals without previous exposure to alloantigen. Proposed mechanisms for the generation of alloreactive memory T cells in the absence of alloantigen include cross-reactivity following acute or chronic viral infection in a process termed heterologous immunity and through homeostatic expansion in response to lymphopenia. Understanding the signals that allow alloreactive memory T cells to persist long-term may suggest new strategies for clinical tolerance. Homeostasis of memory T cells is mediated through a combination of long-term survival of individual cells and cell turnover. These two processes are controlled via extracellular signals recognized by the clonotypic T cell receptor (TCR) and cytokine receptors. The relative contribution of TCR signals and cytokine receptor generated signals may vary depending on the nature of the immunogen, however the specific intracellular signaling pathways required for homeostasis have not been well defined. The overriding hypothesis of this proposal is that the T cell receptor mediated signaling requirements for memory T cell homeostasis and for heterologous immunity differ depending on whether a memory cell is generated by acute viral infection, by chronic viral infection, or antigen-independent events. To address this hypotheses, we have developed a novel in vivo murine model which allows temporally controlled genetic deletion in memory T cells of a key proximal signaling molecule downstream of TCR signaling, the SH2 domain containing leukocyte phosphoprotein of 76 kilodaltons (SLP-76). SLP-76 conditionally deficient T cells offer a unique model for studying memory T cells that were generated with an intact TCR signaling apparatus but lack the ability to transduce either antigen-specific or tonic TCR signals. Our preliminary data show that in contrast to non-manipulated memory phenotype T cells, SLP-76 deficient memory phenotype T cells fail to undergo homeostatic division in an intact host. We propose to define and dissect the effect of infection on homeostasis of memory T cells and transplantation by combining viral infection models with conditional gene deletion and studies on transplantation tolerance. PUBLIC HEALTH RELEVANCE: Immune memory is a hallmark of adaptive immune system and conveys the ability to respond faster and better when an individual is infected for a second time with the same infectious agent (i.e. virus). Immune memory requires infection-specific white blood cells termed lymphocytes to persist for the life of the individual in the absence of ongoing infection. Due of cross-reactivity of some memory T cells, previous viral infection can result in worse outcomes in experimental transplantation of solid organs. The goals of this application are to better understand how memory T cells that are made to fight off infection can adversely affect transplantation and persist to provide long-term immunity.

描述（由申请人提供）：虽然在啮齿动物模型中诱导长期耐受性相对容易，但将这些方案转化为高等脊椎动物和临床医学一直很困难。与小鼠不同，人类经常暴露于病毒病原体中，从而导致短暂性淋巴细胞减少和免疫记忆的产生。人类移植的一个已知障碍是大量的同种异体记忆T细胞，即使在那些以前没有接触过同种异体抗原的个体中也是如此。在没有同种异体抗原的情况下，产生同种异体记忆T细胞的机制包括急性或慢性病毒感染后的异源免疫过程中的交叉反应性，以及淋巴细胞减少反应中的稳态扩张。了解允许同种反应性记忆T细胞长期存在的信号可能为临床耐受提供新的策略。记忆T细胞的内稳态是通过个体细胞的长期存活和细胞周转的结合来调节的。这两个过程是通过克隆型T细胞受体（TCR）和细胞因子受体识别的细胞外信号来控制的。TCR信号和细胞因子受体产生的信号的相对贡献可能因免疫原的性质而异，然而，维持体内平衡所需的特定细胞内信号通路尚未得到很好的定义。该提议的最重要假设是，记忆T细胞稳态和异源免疫的T细胞受体介导的信号要求取决于记忆细胞是由急性病毒感染、慢性病毒感染还是抗原非依赖性事件产生的。为了解决这一假设，我们开发了一种新的小鼠体内模型，该模型允许暂时控制记忆T细胞中TCR信号下游关键近端信号分子的遗传缺失，SH2结构域含有76千顿的白细胞磷酸化蛋白（SLP-76）。SLP-76条件缺陷T细胞为研究记忆T细胞提供了一个独特的模型，记忆T细胞是由完整的TCR信号装置产生的，但缺乏转导抗原特异性或补性TCR信号的能力。我们的初步数据显示，与非操纵记忆表型T细胞相比，SLP-76缺陷记忆表型T细胞在完整宿主中无法进行稳态分裂。我们建议通过结合病毒感染模型、条件基因缺失和移植耐受研究来定义和剖析感染对记忆T细胞和移植稳态的影响。