Lymph Node Structure and Function in Tolerance: Role of Laminins

项目摘要/摘要 然而，Foxp3调节性T细胞(Treg)是移植耐受所必需的，然而，无论何时何地，它们 是否被诱导和激活仍不确定。在共刺激阻断诱导耐受期间，幼稚T细胞 迁移到淋巴结(LN)，但不迁移到脾，在那里它们受到同种异体抗原提呈的刺激 浆细胞样树突状细胞(PDC)，并分化为诱导的Treg(ITreg)。我们已经确定了粘附力 趋化因子分子通过引导Treg在体内的局部积累来协调耐受性 LN的皮质脊(CR)，可见高内皮微静脉(HEV)。混合动力汽车是主要的 T细胞贩运的把关人。总体而言，原始T细胞迁移到CR并成为iTreg，而T细胞 变得无能或凋亡转移到LN的其他区域。因此，需要唯一的LN域 耐受性iTreg的产生和活性。总体假设是这个领域是容忍度所必需的， 目标是定义规范这一结构的关键事件，并可用于容忍。 在这个特殊的LN结构域中，基质纤维层粘连蛋白α4：α5的比率决定了对 同种异体抗原。HEV和CR周围的层粘连蛋白直接指示T细胞的命运，成为T细胞命运的守门人 细胞进入，转换为iTreg，以及后来的T细胞队列的命运，层粘连蛋白α4：α5的高比率有利于 宽容。层粘连蛋白α4(称为αβγ链411)促进CD4T细胞和CD8T细胞的运动和跨内皮细胞 和间质迁移到HEV和CR，促进Foxp3表达和iTreg成熟，并抑制 效应器T细胞分化。相反，层粘连蛋白α5(或511)抑制向HEV的迁移，但共刺激T细胞 增殖和炎症性Th17。T细胞利用整合素α6和α-Ddystrocan识别层粘连蛋白α5 (αDG)受体和αDG-层粘连蛋白α5特异性地诱导Th17.针对这些受体的抗体可延长移植物 存活并增强iTreg向CR的迁移。我们将这些概念推广到其他模型(结肠炎、肿瘤 免疫、慢性排斥、疫苗接种)，在每个病例中，免疫与层粘连蛋白α4：α5下降相关 在这种情况下，需要增加比率，而容忍则需要增加比率。 总之，我们的新数据表明，基质细胞调节层粘连蛋白α4：α5的比例，并控制 免疫反应对炎症和免疫(低比率)或抑制和耐受(高比率)的命运 比率)。我们的具体假设是LN基质细胞整合免疫信号，从而调节层粘连蛋白 结构，而这种整合是引导免疫反应和同种异体移植的最终共同途径 结果。因此，层粘连蛋白的重塑是先天免疫的一个方面，通过免疫信号刺激基质。 细胞(FRC、LEC、BEC)改变LN结构，进而决定获得性免疫。这个 推论是：1)层粘连蛋白调节对炎症和免疫的反应，从而导致促- 炎症性LN结构或免疫性瘢痕的病理反应；2)层粘连蛋白调节 对抑制和耐受的反应，并导致动态平衡和促耐受的LN结构。

Project Summary/Abstract Foxp3+ regulatory T cells (Treg) are required for transplant tolerance, however, where and when they are induced and activated remains uncertain. During costimulatory blockade induced tolerization, naïve T cells migrate to the lymph node (LN), but not the spleen, where they are stimulated by alloantigen presenting plasmacytoid dendritic cells (pDC), and differentiate into induced Treg (iTreg). We have identified the adhesion and chemokine molecules which orchestrate tolerance by directing the localized accumulation of Treg in the cortical ridge (CR) of the LN where the high endothelial venules (HEV) are present. HEV are the main gatekeeper of T cell trafficking. Overall, naive T cells migrate to the CR and become iTreg, while T cells that become anergic or apoptotic migrate to other regions of the LN. Thus, a unique LN domain is required for the generation and activity of tolerogenic iTreg. The overall hypothesis is that this domain is required for tolerance, and the goal is to define the key events that regulate this structure and can be leveraged for tolerization. In this specialized LN domain the stromal fiber laminin α4:α5 ratios determine the response to alloantigen. Laminins surrounding the HEV and CR act as gatekeepers for T cell fate by directly instructing T cell entry, conversion to iTreg, and the fate of later T cell cohorts, with a high laminin α4:α5 ratio favoring tolerance. Laminin α4 (termed 411 for αβγ chains) promotes CD4 and CD8 T cell motility and transendothelial and interstitial migration into the HEV and CR, promotes Foxp3 expression and iTreg maturation, and inhibits effector T cell differentiation. In contrast, laminin α5 (or 511) inhibits migration into HEV, yet costimulates T cell proliferation and inflammatory Th17. T cells recognize laminin α5 using both integrin α6 and α-dystroglycan (αDG) receptors, and αDG-laminin α5 specifically induces Th17. Antibodies to these receptors prolong graft survival and enhance iTreg migration to the CR. We generalized these concepts in other models (colitis, tumor immunity, chronic rejection, vaccination), and in each case immunity correlated with decreased laminin α4:α5 ratios, while tolerance required an increased ratio. Altogether, our new data indicate that stromal cells regulate the LN laminin α4:α5 ratio and control the fate of the immune response to inflammation and immunity (low ratio) or to suppression and tolerance (high ratio). Our specific hypothesis is that LN stromal cells integrate immune cues and thus regulate laminin structures, and this integration is a final common pathway that channels the immune response and allograft outcomes. Thus, remodeling of laminins is a facet of innate immunity whereby immune cues stimulate stromal cells (FRC, LEC, BEC) to modify LN structure, which subsequently determines adaptive immunity. The corollaries are: 1) laminins regulate the response to inflammation and immunity, which results in pro- inflammatory LN structures or even the pathologic response of immunologic scarring; and 2) laminins regulate the response to suppression and tolerance and result in homeostatic and pro-tolerogenic LN structures.