Lymphoid Structure in Tolerance: Role of Stromal Cells

描述(申请人提供)：实现耐受仍然是移植免疫学最重要的目标。使用共刺激阻断的耐受模型是最可靠和临床相关的方法之一。对协同刺激阻断过程中的耐受机制，如无能、细胞凋亡和调节性T细胞(Treg)，已知很多。然而，通常很难诱导和保持强大的耐受性，以抵抗外部干扰。这表明，决定耐受性的其他重要免疫学机制仍有待阐明。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控过程。在几篇重要的文献中，我们证明了耐受性是通过特定的同种异体抗原提呈细胞与NA抗原特异性T细胞的精确相互作用而在淋巴结(LN)启动的，以产生调节性抑制性T细胞。这种相互作用发生在LN中，并且 依赖于许多分子信号的错综复杂的协调。随后抑制性T细胞的运输至关重要，因此，与通过血液和淋巴结节的迁移相比，从血液到移植物再到淋巴管的迁移具有独特的抑制作用。在这个项目的第一个资助期，我们阐明了一些新的和意想不到的机制，这些机制是诱导耐受所必需的，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，注定要成为抑制者的T细胞只在LN的一个区域被发现，称为皮质脊。相反，注定要成为效应者的T细胞散布在LN各处。皮质脊特别富含特殊纤维和间质细胞，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。这些观察结果表明，皮质脊的FRC调节LN结构和功能的关键方面，是T细胞和抗原提呈细胞定位和功能的关键控制元件，因此决定了免疫和耐受之间的选择。

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 anergy, 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 na¿ve 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. In the first funding period for this project, we 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 reticular cells (FRC), suggesting a uniqu function or arrangement for these cells and their associated fibers. These observations suggest the hypothesis that the FRC of the cortical ridge regulate critical aspects of LN structure and function, are key controlling elements for the positioning and function of T cells and antigen presenting cells, and therefore determine the choice between immunity versus tolerance.