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。子项目及 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，我们证实了CD 137介导的信号传导（一种导致T细胞保护性免疫应答的事件）在适当条件下诱导T细胞功能抑制（无反应性）。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，我们已经了解到CD 137介导的无反应性依赖于T细胞上的CD 137表达，但尽管必要，但不足以诱导T细胞无反应性。T细胞中的⑶ 137信号传导导致凋亡诱导死亡受体⑶ 95（Fas）的上调。 在研究其他造血细胞谱系的功能时，我们发现树突状细胞（DC）中的CD 137介导的信号传导对于诱导病毒特异性T细胞的无能是至关重要的，并且表达CD 137的所有主要DC亚群都可以诱导T细胞无能。无反应性T细胞最终通过称为活化诱导的细胞死亡（AICD）的过程被删除，并且该过程也是DC和CD 137依赖性的，因为它诱导T细胞上调和释放可溶性Fas配体。 通过研究了解DC中的CD 137信号如何改变它们的功能，使得这些抗原呈递细胞导致无反应性和AICD的诱导，而不是正常的幼稚T细胞的激活，我们发现DC中的CD 137信号导致转录因子Stat 3的快速激活（磷酸化）。其他人先前已经表明，DC中的Stat 3信号传导在维持免疫自身耐受中起着关键作用。目前的研究正在进行中，以确定CD 137激活Stat 3的生化途径。

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 CD137-mediated signaling, an event that leads to protective immune responses by T cells, under appropriate conditions induced suppression of T cell function (anergy). By adoptive transfer of CD137-sufficient SMARTA transgenic CD4 T cells and CD137-sufficient P14 TCR transgenic CD8 T cells into CD137-deficient mice we have learned that CD137-mediated anergy was dependent on CD137 expression on T cells, but while necessary, was insufficient to induce T cell anergy. CD137 signaling in T cells led to up- regulation of the apoptosis-inducing death receptor CD95 (Fas). While examining the function of other hematopoietic cell lineages, we found that CD137-mediated signaling in dendritic cells (DC) was critical to the induction of anergy in virus-specific T cells, and that all major subsets of DCs expressing CD137 could induce T cell anergy. Anergic T cells are ultimately deleted through a process known as activation-induced cell death (AICD) and this process too is DC and CD137-dependent as it induces the upregulation and release of soluble Fas ligand by T cells. From studies geared to understand how CD137 signaling in DCs altered their function such that these antigen-presenting cells led to the induction of anergy and AICD rather than as is normal, the activation of na¿ve T cells, we found that CD137 signaling in DCs led to the rapid activation (phosphorylation) of the transcription factor, Stat3. Others had previously shown that Stat3 signaling in DCs plays a critical role in the maintenance of immune self-tolerance. Current studies are currently underway to indentify the biochemical pathway through which CD137 activates Stat3.