Novel costimulatory pathways required for T cell regulation

T细胞耐受与免疫的控制在一定程度上依赖于共刺激和共抑制受体的信号，这些受体控制T细胞的各种活动，并调节调节性T细胞(Treg)和调节性树突状细胞的抑制能力。4-1BB(CDI 37，ILA，TNFRSF9)是肿瘤坏死因子受体(TNFR)超家族成员之一，是活化T细胞上的可诱导共刺激分子。它是公认的配体，命名为4-1 BBL(TNFSF9)，是肿瘤坏死因子超家族的成员。与4-1 BB在免疫中的积极作用相反，我们发现了一种新的不依赖于与4-1 BBL相互作用的抑制作用。在基因缺陷的动物中，4-1BB的缺失导致T细胞对特定抗原的反应性增强而不是被抑制，4-1BB缺陷的小鼠自发产生自身免疫型表型，并在粘膜界面发生慢性炎症，这种表型在4-1BBL缺陷的小鼠中看不到。我们发现在缺乏4-1BB的小鼠粘膜表面存在Foxp3+Treg的缺陷，粘膜树突状细胞不能表现出正常的调节活性并诱导Foxp3+Treg的发展。我们将检验这一假设，即4-1 BB对Treg和调节性树突状细胞活性的调节是其促进免疫耐受的原因，并追求4-1 BB与以前未被认识的新配体合作导致调节传统T细胞免疫的想法。我们已经发现4-1BB可以与Galecfin-3和Galecfin-9这两个已报道的抑制分子结合，我们将确定4-1BB/Galectin相互作用是否解释了4-1BB对T细胞反应性的负调控。

The control of T cell tolerance versus immunity in part relies on signals from co-stimulatory and co-inhibitory receptors that control various activities of T cells and modulate the suppressive capacity of regulatory T cells (Treg) and regulatory dendritic cells. 4-1 BB (CDI 37, ILA, TNFRSF9), a member of the tumor-necrosis factor receptor (TNFR) super-family, has been characterized as an inducible co-stimulatory molecule on activated T cells. It's recognized ligand, termed 4-1 BBL (TNFSF9), is a member ofthe TNF super-family. Opposed to the positive role that 4-1 BB plays in immunity, we have found a novel inhibitoryrole that does not rely on interaction with 4-1 BBL. The absence of 4-1BB, in gene-deficient animals, leads to an enhanced rather than suppressed responsiveness of T cells to specific antigen, and 4-1BB-deficient mice spontaneously generate autoimmune-type phenotypes with chronic inflammation at the mucosal interfaces, a phenotype not seen in 4-1 BBL-deficient mice. We have found a deficit of Foxp3+ Treg at the mucosal surfaces in mice lacking 4- 1BB, and an inability of mucosal dendritic cells to display normal regulatory activity and induce the development of Foxp3+ Treg. We will test the hypothesis that 4-1 BB modulation ofthe activity of Treg and regulatory dendritic cells accounts for its role in promoting immune tolerance, and pursue the idea that 4-1 BB partnering with new, previously unrecognized, ligands results in regulation of conventional T cell immunity. We have found that 4-1 BB can bind to galecfin-3 and galecfin-9, two reported suppressive molecules, and we will determine whether 4-1BB/galectin interactions account for 4-1 BB negatively regulating T cell responsiveness.