Lymph Node Structure and Function in Tolerance: Role of Laminins

项目总结/摘要 Foxp 3+调节性T细胞（Treg）是移植耐受所必需的，然而，在何时何地， 是如何被诱导和激活的仍然不确定。在共刺激阻断诱导的耐受化过程中，幼稚T细胞 迁移到淋巴结（LN），但不是脾，在那里它们受到同种异体抗原呈递的刺激 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 和趋化因子分子，其通过引导Treg在细胞中的局部积累来协调耐受性。 LN的皮质嵴（CR），其中存在高内皮微静脉（HEV）。HEV是主要的 T细胞运输的守门人总的来说，初始T细胞迁移到CR并成为iTreg，而 变得无反应性或凋亡，迁移到LN的其他区域。因此，需要唯一的LN结构域用于所述结构域。 致耐受性iTreg的产生和活性。总体假设是，该域是宽容所需的， 目标是定义调节这种结构的关键事件，并可以用于容忍。 在这个特殊的LN结构域中，基质纤维层粘连蛋白α4：α5的比例决定了对 同种抗原HEV和CR周围的层粘连蛋白通过直接指导T细胞的命运来充当T细胞命运的守门人。 细胞进入，转化为iTreg，以及后期T细胞群的命运，高层粘连蛋白α4：α5比率有利于 宽容层粘连蛋白α4（αβγ链称为411）促进CD 4和CD 8 T细胞运动和跨内皮细胞 和间质迁移进入HEV和CR，促进Foxp 3表达和iTreg成熟，并抑制 效应T细胞分化。相反，层粘连蛋白α5（或511）抑制迁移到HEV，但共刺激T细胞 增殖和炎性Th 17。T细胞通过整合素α6和α-肌营养不良蛋白聚糖识别层粘连蛋白α5 （αDG）受体，α DG-层粘连蛋白α5特异性诱导Th 17。这些受体的抗体延长移植物 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）中 免疫、慢性排斥、疫苗接种），并且在每种情况下，免疫与层粘连蛋白α4：α5降低相关 比率，而公差则需要增加比率。 总之，我们的新数据表明，基质细胞调节LN层粘连蛋白α4：α5的比例，并控制LN的增殖。 免疫应答对炎症和免疫（低比率）或对抑制和耐受（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 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。 成果。因此，层粘连蛋白的重塑是先天免疫的一个方面，由此免疫信号刺激间质 细胞（FRC，LEC，BEC）来修饰LN结构，这随后决定了适应性免疫。的 推论是：1）层粘连蛋白调节对炎症和免疫的反应，这导致前 炎症LN结构或甚至免疫瘢痕的病理反应;和2）层粘连蛋白调节 对抑制和耐受应答，并导致稳态和促耐受性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.