Signals Affecting Homestasis and Tolerance in Memory T Cells

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是困难的。与小鼠不同，人类经常暴露于病毒病原体，导致短暂的淋巴细胞减少症和免疫记忆的产生。人类移植的一个已知障碍是大量的同种异体反应性记忆T细胞，即使在那些先前没有暴露于同种异体抗原的个体中也是如此。提出的在不存在同种异体抗原的情况下产生同种异体反应性记忆T细胞的机制包括在称为异源免疫的过程中的急性或慢性病毒感染后的交叉反应性以及通过响应于淋巴细胞减少的稳态扩增。了解允许同种异体反应性记忆T细胞长期存在的信号可能会为临床耐受提出新的策略。记忆T细胞的稳态是通过单个细胞的长期存活和细胞更新的组合来介导的。这两个过程通过克隆型T细胞受体（TCR）和细胞因子受体识别的细胞外信号来控制。TCR信号和细胞因子受体产生的信号的相对贡献可以根据免疫原的性质而变化，然而，体内平衡所需的特定细胞内信号传导途径尚未明确定义。该提议的最重要的假设是，记忆T细胞稳态和异源免疫的T细胞受体介导的信号传导要求根据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而不同。为了解决这一假设，我们已经开发了一种新的体内小鼠模型，其允许在TCR信号传导下游的关键近端信号传导分子（含有76千道尔顿白细胞磷蛋白（SLP-76）的SH 2结构域）的记忆T细胞中暂时控制遗传缺失。SLP-76条件性缺陷T细胞为研究记忆T细胞提供了一个独特的模型，这些记忆T细胞是用完整的TCR信号传导装置产生的，但缺乏识别抗原特异性或紧张性TCR信号的能力。我们的初步数据显示，与非操纵的记忆表型T细胞相反，SLP-76缺陷型记忆表型T细胞在完整宿主中不能进行稳态分裂。我们建议通过结合病毒感染模型和条件性基因缺失以及移植耐受的研究来定义和剖析感染对记忆T细胞和移植的稳态的影响。

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.