Regulation of avidity in T lymphocytes

 描述（由申请人提供）：越来越清楚的是，T细胞命运是多方面和高度调节的分化过程的结果。这个过程决定了细胞的多种特性，包括效应子功能、存活和功能性亲合力的范围。 功能性亲合力是体内功效的基本决定因素。目前，我们对亲合力的分子调控还远没有完全了解。我们以前的结果表明，一个单独的T细胞可以调节亲合力响应刺激信号。本研究的总体目标是确定CD 8 + T细胞调节亲合力的机制，以及与确定亲合力设定点相关的表观遗传变化。目标1。确定高肽与低肽结合对IL-4和IFNγ产生和信号传导的调节。我们的初步数据支持CD 8 + T细胞中的亲合力调节受T细胞衍生的IL-4和IFNγ的联合作用调节的假设。我们提出，与高与低量的肽/MHC的相遇导致T细胞的细胞因子产生和/或它们对这些细胞因子的响应性的差异。该模型的创新之处在于它提出了一种基于自分泌细胞因子的亲合力自调节。我们的研究将 检验这些单独的细胞因子以不同的水平产生或具有依赖于存在的肽/MHC的量的抑制动力学的假设。我们还将检验细胞因子受体表达和/或反应性在分化为高与低亲合力效应物的细胞中受到差异调节的假设。目标2.确定细胞因子和TCR信号如何在经历功能性亲合力调节的细胞中诱导表观遗传变化。表观遗传变化导致通过细胞分裂维持基因表达程序，这与我们系统中效应细胞中诱导的稳定功能亲合力设定点一致。最近的研究表明甲基化在CD 8+效应细胞的程序化分化中起关键作用。 我们相信这些结果为检查甲基化在建立亲合力设定点中的作用提供了强有力的理论基础。这些研究将提供新的信息，在分化的CD 8 + T细胞的功能亲合力的控制。这些研究的结果可能最终为旨在操纵体内T细胞反应的新治疗干预打开大门。

 DESCRIPTION (provided by applicant): It is increasingly clear that T cell fate is the result of a multi-faceted and highly regulated process of differentiation. This process dictates multiple properties of the cell including the range of effector functions, survival, and functional avidity. Functional avidity is a fundamental determinant of in vivo efficacy. At present, we are far from a complete understanding of the molecular control of avidity. Our previous results demonstrated that an individual T cell can modulate avidity in response to the stimulatory signal. The overall goals of the studies presented here are to determine the mechanism by which CD8+ T cells modulate avidity, and the epigenetic changes associated with determination of the avidity set point. Aim 1. To define the regulation of IL-4 and IFNγ production and signaling as a result of engagement of high versus low peptide. Our preliminary data support the hypothesis that avidity modulation in CD8+ T cells is regulated by the combined effects of T cell derived IL-4 and IFNγ. We propose that encounter with high vs. low amounts of peptide/MHC results in divergence in cytokine production by T cells and/or their responsiveness to these cytokines. This model is innovative in that it suggests an autocrine cytokine based self tuning of avidity. Our studies will test the hypothesis that these individual cytokines are produced at distinct levels or with differet kinetics depending on the amount of peptide/MHC present. We will also test the hypothesis that cytokine receptor expression and/or responsiveness is differentially regulated in cells that are differentiating into high vs. low avidity effectors. Aim 2. To determine how cytokine and TCR signals induce epigenetic changes in cells undergoing functional avidity modulation. Epigenetic changes result in maintenance of gene expression programs through cell division, consistent with the stable functional avidity set point induced in effector cells in our system. Recent studie demonstrate the critical role of methylation in programming differentiation of CD8+ effector cells. We believe these results provide strong rationale for examining the role or methylation in establishing the avidity set point. These studies will provide novel information regarding the control of functional avidity in differentiating CD8+ T cells. The results from these studies may ultimately open the door to new therapeutic interventions aimed at manipulating T cell responses in vivo.