Lymph Node Structure and Function in Tolerance: Role of Laminins

 描述（由申请人提供）：实现耐受仍然是移植免疫学中最重要的目标。采用共刺激阻断的耐受模型是最稳健和临床相关的方法之一。人们对共刺激阻断过程中起作用的耐受机制了解很多，例如能量、细胞凋亡和调节性 T 细胞 (Treg)。然而，通常很难诱导和维持抵抗外部扰动的稳健耐受性。这表明决定耐受性的其他重要免疫机制仍有待阐明。 我们的实验室专注于迁移、运输和次级淋巴器官结构的作用，作为决定免疫相互作用是否导致免疫与耐受的关键调节过程。在几篇重要出版物中，我们证明了淋巴结 (LN) 中的耐受性是通过特定同种抗原呈递细胞与幼稚抗原特异性 T 细胞的精确相互作用产生调节性抑制性 T 细胞而启动的。这种交互发生在 LN 中，并且 依赖于许多分子信号的复杂协调。抑制性 T 细胞的后续运输至关重要，因此与通过血液和淋巴结的迁移相比，从血液迁移到移植物，然后进入淋巴管具有独特的抑制作用。 我们已经阐明了耐受诱导所需的几种新颖且意想不到的机制，这些机制与 LN 结构与淋巴细胞反应的细胞和分子机制的相互作用有关。结果表明，注定要成为抑制因子的 T 细胞仅存在于 LN 的一个区域（称为皮质嵴）。相比之下，注定要成为效应细胞的 T 细胞分散在整个淋巴结中。皮质脊特别富含特殊纤维和基质细胞，称为成纤维网状细胞（FRC），表明这些细胞及其相关纤维具有独特的功能或排列。 这些观察结果共同得出这样的假设：皮质嵴的 LN 域（包含 HEV 及其周围的基质纤维）是耐受的主要位点。在耐受过程中，幼稚 T 细胞和呈递 pDC 的同种抗原进入该区域并保留在基质纤维内的 HEV 周围。需要精确的基质细胞功能和纤维排列来创建和维持 Treg 诱导所需的微环境。这些 Treg 持续存在于这个高流量区域，并充当穿过 HEV 的新 T 细胞的看门人。当新的初始抗原特异性 T 细胞进入 LN 时，这些 Treg 调节它们的迁移、激活和命运，因此 Treg 决定耐受性或免疫性。

 DESCRIPTION (provided by applicant): Achieving tolerance remains the most important goal in transplantation immunology. Models of tolerance employing co-stimulatory blockade are among the most robust and clinically relevant approaches. Much is known about the mechanisms of tolerance that are operative during co-stimulatory blockade, such as energy, apoptosis, and regulatory T cells (Treg). However, it is often difficult to induce and maintain robust tolerance that is resistant to external perturbations. This suggests that other important immunologic mechanisms that determine tolerance remain to be elucidated. Our laboratory has focused on the role of migration, trafficking and secondary lymphoid organ structure as crucial regulatory processes that determine whether immune interactions result in immunity versus tolerance. In several key publications we demonstrated that tolerance is initiated in lymph nodes (LN) through the precise interaction of specific alloantigen presenting cells with naïve antigen specific T cells to generate regulatory suppressive T cells. This interaction occurs in the LN, and is dependent on the intricate coordination of many molecular signals. Subsequent trafficking of the suppressive T cells is critical, so that migration from blood to grafts and then into lymphatic has distinct and unique suppressive effects, in comparison to migration through blood and LNs. We have elucidated several novel and unexpected mechanisms that are required for tolerance induction, and these mechanisms relate to the interaction of LN structure with the cellular and molecular mechanisms of lymphocyte responses. The results demonstrate that T cells destined to become suppressors are found in only one region of the LN, called the cortical ridge. In contrast, T cells destined to become effectors are found scattered throughout the LN. The cortical ridge is particularly rich in specialized fibers and stromal cells, called fibroblastic reicular cells (FRC), suggesting a unique function or arrangement for these cells and their associated fibers. Together these observations lead to the hypothesis that the LN domain of the cortical ridge, that encompasses the HEV and their surrounding stromal fibers, is a major locus for tolerization. During tolerization naïve T cells and alloantigen presenting pDC enter this domain and remain around the HEV within the stromal fibers. Precise stromal cell function and fiber arrangement are required to create and maintain the microenvironment necessary for Treg induction. These Treg persist in this high-traffic region and act as gatekeepers for new T cells that traverse the HEV. These Treg regulate the migration, activation, and fate of new naïve antigen specific T cells as they enter the LN, and thus the Treg determine tolerance or immunity.