Lymph Node Structure and Function in Tolerance: Role of Laminins

 描述（由申请人提供）：实现耐受性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。关于在共刺激阻断期间起作用的耐受机制，如能量、凋亡和调节性T细胞（Treg），已经知道很多。然而，通常难以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。 我们的实验室一直专注于迁移，贩运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。在几个关键的出版物中，我们证明了通过特异性同种异体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，在淋巴结（LN）中引发耐受。这种相互作用发生在LN中， 依赖于许多分子信号的复杂协调。抑制性T细胞的后续运输是至关重要的，因此与通过血液和淋巴结的迁移相比，从血液到移植物然后到淋巴的迁移具有明显和独特的抑制作用。 我们已经阐明了一些新的和意想不到的机制，需要耐受诱导，这些机制涉及LN结构的相互作用与淋巴细胞反应的细胞和分子机制。结果表明，注定成为抑制因子的T细胞只在LN的一个区域中发现，称为皮质脊。相反，T细胞注定成为效应被发现分散在整个LN。皮质嵴特别富含特化纤维和基质细胞，称为成纤维细胞网状细胞（FRC），这表明这些细胞及其相关纤维具有独特的功能或排列。 总之，这些观察结果导致的假设，LN域的皮质嵴，包括HEV及其周围的基质纤维，是一个主要的耐药位点。在耐受化过程中，初始T细胞和同种异体抗原呈递pDC进入该结构域并保持在基质纤维内的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细胞的守门人。这些Treg调节新的幼稚抗原特异性T细胞进入LN时的迁移、活化和命运，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.