Expression and function of the TLRs on T cells

Toll样受体（TLR）在先天性和适应性免疫中起着不可或缺的作用。TLR的连接激活 天然免疫系统的细胞，诱导诸如吞噬作用和IFN-α和IFN-b分泌的功能。 TLR-连接还充当先天性和适应性免疫系统之间的桥梁。TLR刺激 DC和巨噬细胞诱导炎性细胞因子如IL-12的产生，并上调IL-12的表达。 MHC II类和共刺激配体如CD 40和CD 86，这些反应中的大多数需要 通过衔接子信号分子MyD 88传递的信号。TLR和MyD 88在APC中的作用 虽然已经建立了良好的关系，但令人惊讶的是，关于它们在T细胞上的表达和潜在功能知之甚少。 我们实验室的研究表明，在初始CD 4 + CD 25-T细胞活化后， T细胞。这些TLR的连接通过MyD 88激活几种下游信号传导途径，包括NF-κ B和NF-κ B。 kB、p38 JNK和ERK。在功能上，这导致增强的T细胞存活，并提供共刺激， 次优TCR连接。新的数据还表明，MyD 88在T细胞中的体内表达可能与T细胞中MyD 88的表达有关。 对病原体弓形虫的保护性免疫反应所必需的。 我们的工作假设是，T细胞上的TLR和MyD 88信号传导是细胞凋亡的重要贡献者。 免疫反应。为此，本研究计划的长期目标是定义表达 和TLR在T细胞上的功能。在具体的目标#1中，我们将描述控制信号的特征。 TLR在T细胞上的表达和上调，以及TLR和 MyD 88用于介导其作用。具体目标#2将使用来自TCR转基因小鼠的细胞， 体外和体内过继转移系统进行详细检查TLR的影响， MyD 88在诱导活化和共刺激分子、细胞因子产生或 偏斜和效应器/记忆分化和响应性。这种方法将允许精确的 TLR刺激T细胞可以做什么。在具体的目标#3中，我们将询问哪些功能 在目的#2中鉴定的TLR和MyD 88在体内免疫应答期间起作用。为此，我们将 使用MyD 88敲除小鼠和骨髓嵌合体以及过继转移系统在体内产生 模型中只有T细胞缺乏MyD 88。根据我们的初步数据，我们将使用这些 模型，以评估对弓形虫的反应，并将MyD 88缺陷小鼠回交到 TCR转基因背景，使我们能够跟踪单个T细胞的命运，因为它们响应于 同种异体抗原在移植模型中的体内表达。

Toll-like receptors (TLRs) play an integral role in innate and adaptive immunity. Ligation of TLRs activates cells of the innate immune system, inducing functions such as phagocytosis and IFN-a and IFN-b secretion. TLR-ligation also serves as a bridge between the innate and adaptive immune systems. TLR stimulation of DCs and macrophages induces the production of inflammatory cytokines such as IL-12, and upregulation of MHC class II and costimulatory ligands such as CD40 and CD86, and most of these responses require signals delivered through the adaptor signaling molecule MyD88. While roles for TLRs and MyD88 on APCs are well-established, surprisingly little is known about their expression and potential function on T cells. Studies from our laboratory show that several TLRs are expressed following activation of naive CD4+CD25- T cells. Ligation of these TLRs activates, via MyD88, several downstream signaling pathways, including NF- kB, p38 JNK, and ERK. Functionally, this leads to enhanced T cell survival and provides costimulation with sub-optimal TCR ligation. New data also indicates that in vivo expression of MyD88 in T cells may be required for a protective immune response to the pathogen Toxoplasma gondii. Our working hypothesis is that TLR and MyD88 signaling on T cells are important contributors to cellular immune responses. To this end, the long-term goals of this research program are to define the expression and function of TLRs on T cells. In specific aim #1 we will characterize the signals which govern the expression and upregulation of TLRs on T cells, and the downstream signaling pathways which TLRs and MyD88 use to mediate their effects. Specific aim #2 will use cells from TCR transgenic mice coupled with in vitro and in vivo adoptive transfer systems to conduct a detailed examination of the effects of TLR and MyD88 activation of T cells on induction of activation and costimulatory molecules, cytokine production or skewing, and effector/memory differentiation and responsiveness. This approach will allow for precise definition of what TLR stimulation of T cells can do. In specific aim #3 we will then ask which of the functions identified for TLRs and MyD88 in aim #2 are operative during in vivo immune responses. To do so, we will use MyD88 knockout mice and bone-marrow chimeras and adoptive transfer systems to create in vivo models in which only T cells are deficient in MyD88. Based on our preliminary data, we will use these models to assess responses to Toxoplasma gondii, and will also backcross the MyD88-deficient mice onto TCR transgenic backgrounds to enable us to track the fate of individual T cells as they respond to alloantigen in vivo in transplantation models.