CD137 SIGNALS IN DC DURING AG-PRIMING INDUCES TOLERANCE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在本报告期内，我们证实抗CD 137介导的抑制可在CD 8 T细胞以及CD 4 T细胞中诱导。通过将CD 137-足够SMARTA转基因CD 4 T细胞和CD 137-足够P14 TCR转基因CD 8 T细胞过继转移到CD 137缺陷小鼠中，我们发现抗CD 137引起的抑制诱导部分依赖于T细胞上的CD 137表达，而不是完全独立，如我们先前报道的。CD 137信号传导对T细胞的贡献被发现是诱导凋亡的死亡受体CD 95（Fas）的上调。 此外，我们发现，CD 137介导的信号转导在pDC和mDC中是诱导病毒特异性CD 8 T细胞耐受的关键，并且DC通过诱导可溶性Fas配体的释放而有助于诱导CD 8 T细胞耐受。我们发现，虽然DC诱导可溶性Fas配体的释放，他们不是这种蛋白质的来源。 我们的研究目前集中在鉴定负责Fas配体释放的细胞谱系。在其他研究中，我们发现CD 137及其同源配体起着守门人的作用，并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并进入外周的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.