Interactions between dendritic cells and regulatory T cells.

调节性T细胞（Tcells）是表达转录因子Foxp 3的CD 4+辅助性T细胞的亚群，并且可以通过多种机制抑制免疫应答，包括细胞因子产生和DC功能的下调。在大多数情况下，TCLs不增殖，但我们以前已经表明，骨髓树突状细胞（DC）是专门的抗原呈递细胞刺激TCLs的增殖和扩增。重要的是，由DC扩增的TcR维持Foxp 3表达，并且在体外和体内仍然是抑制性的。具体来说，我们证明了DC扩增的TcR可以逆转NOD小鼠的糖尿病。然后我们假设，正如常规T细胞被DC和抗原最佳地刺激一样，用DC刺激的T细胞将上调对其抑制功能重要的转录物。因此，我们比较了来自用DC刺激的Tcl 3的转录谱与来自静息Tcl 3或用IL-2刺激的Tcl 3的谱。有趣的是，IL-1通路的天然抑制剂在DC刺激的TcB中高度上调。我们现在正在研究IL-1抑制剂对Treg功能和诱导新的Treg的作用。此外，将用TdR培养的DC的转录谱与单独培养的DC进行比较。正如其他人所报道的，我们还观察到与TdR一起培养的DC中参与抗原加工和呈递的转录物下调。我们现在关注的是一小部分转录本，它们在与TdR培养后在DC中上调，但在与原始辅助性T细胞（CD 4 + CD 25-细胞）培养后没有上调。我们开始测试这些转录本对DC功能的作用。 例如，我们发现DC刺激后Treg中IL-1受体拮抗剂（IL-1 Ra）信息高度上调。 为了测试IL-1 Ra是否对Treg功能重要，我们使用来自野生型或IL-1 Ra敲除小鼠的Tclase来治疗自身免疫性结肠炎。 我们发现，敲除Tclase不能阻止结肠炎的进一步发展，如通过体重减轻、组织学和结肠中的IL-1水平所测量的。 我们目前正在跟进这一发现。

Regulatory T cells (Tregs) are a subset of CD4+ helper T cells that express the transcription factor Foxp3 and can suppress immune responses through a variety of mechanisms, including cytokine production and down-modulation of DC function. Under most conditions, Tregs do not proliferate, but we have previously shown that bone marrow dendritic cells (DCs) are specialized antigen presenting cells for stimulating proliferation and expansion of Tregs. Importantly, Tregs expanded by DCs maintain Foxp3 expression and are still suppressive in vitro and in vivo. Specifically, we showed that DC-expanded Tregs can reverse diabetes in NOD mice. We then hypothesized that, just as conventional T cells are optimally stimulated by DCs and antigen, Tregs stimulated with DCs would upregulate transcripts important for their suppressive function. Therefore, we have compared transcriptional profiles from Tregs stimulated with DCs, with profiles from resting Tregs or Tregs stimulated with IL-2. Interestingly, natural inhibitors of the IL-1 pathway were highly upregulated in Tregs stimulated by DCs. We are now studying the role of inhibitors of IL-1 for both Treg function and induction of new Tregs. In addition, transcriptional profiles of DCs that had been cultured with Tregs were compared to DCs cultured alone. As reported by others, we also observed downregulation of transcripts involved in antigen processing and presentation in DCs that had been cultured with Tregs. We have now focused on a small set of transcripts that are upregulated in DCs after culture with Tregs, but not after culture with nave helper T cells (CD4+ CD25- cells). We are beginning to test the role of these transcripts for DC function. For example, we have found that IL-1 Receptor antagonist (IL-1Ra) message is highly upregulated in Tregs after DC stimulation. To test if IL-1Ra is important for Treg function, we used Tregs from either wildtype or IL1Ra knockout mice to treat autoimmune colitis. We found that the knockout Tregs were not able to block further development of colitis, as measured by weight loss, histology, and IL-1 levels in the colon. We are currently following up on this finding.