CD137 SIGNALS IN DC DURING AG-PRIMING INDUCES TOLERANCE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在本报告期间，我们证实，通过过继将CD137充足的SMARTA转基因CD4T细胞和CD137充足的P14 TCR转基因CD8 T细胞转移到CD137缺陷小鼠体内，可以在CD8T细胞和CD8T细胞中诱导抗CD137介导的抑制，并且我们发现抗CD137诱导的抑制作用部分依赖于T细胞上CD137的表达，而不是像我们之前报道的那样完全独立。CD137信号对T细胞的作用是通过上调凋亡诱导死亡受体CD95(Fas)来实现的。 此外，我们还发现CD137介导的PDCs和MDCs信号通路在诱导病毒特异性CD8T细胞耐受中起关键作用，DC通过诱导可溶性Fas配体的释放参与了CD8T细胞耐受的诱导。我们发现，尽管DC诱导了可溶性Fas配体的释放，但它们并不是该蛋白的来源。 我们目前的研究集中在鉴定负责Fas配体释放的细胞谱系。在其他研究中，我们发现CD137及其同源配体作为门守护者，限制了骨髓中早期骨髓生成的程度，这一事件限制了离开骨髓进入外周的DC数量。这种方法将促进我们对艾滋病毒感染等疾病的免疫反应的理解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the current reporting period we confirmed that anti-CD137-mediated suppression could be induced in CD8 T cells, as well as CD4 T. By adoptively transferring CD137-sufficient SMARTA transgenic CD4 T cells and CD137-sufficient P14 TCR transgenic CD8 T cells into CD137-deficient mice and we have found that the induction of suppression caused by anti-CD137 was in part dependent on CD137 expression on T cells, rather than completely independent, as we had previously reported. The contribution made by CD137 signaling to T cells was found to be the upregulation of the apoptosis-inducing death receptor CD95 (Fas). In addition, we found that CD137-mediated signaling in pDCs and mDCs was critical to the induction of tolerance of virus-specific CD8 T cells and that DCs contributed to the induction of CD8 T cell tolerance by inducing the release of soluble Fas ligand. We showed that although DCs induced the release of soluble Fas ligand, they were not the source of this protein. Our studies are presently focused on the identification of the cell lineage that is responsible for the release of Fas ligand. In other studies we have found that CD137 and its cognate ligand function as gate keepers and limit the extent of early myelopoiesis in the bone marrow, an event that limits the numbers of DCs that leave the bone marrow and enter the periphery. This approach will advance our understanding of immune response of conditions such as HIV infection.