Molecular and Physical basis of T Cell Interactions with Non-hematopietic Stroma

描述（由申请方提供）：成纤维细胞网状细胞（FRC）是淋巴结（LN）中非造血基质细胞的主要群体之一，分泌细胞外基质成分以形成致密的网状网络和淋巴引流管道系统。T细胞区由FRC划定，形成支架，为免疫细胞提供必要的指导线索。FRC通过表达CCL19和CCL21以及粘附分子、整合素和糖蛋白来协调免疫细胞迁移。除了迁移之外，FRC维持幼稚T细胞稳态，并且它们具有施加抗原特异性缺失耐受的能力，直接将病毒和自身肽呈递给幼稚CD8 + T细胞。 在这些研究中缺失事件的时间，无论是FRC介导的激活信号到幼稚T细胞的必然结果，还是活化T细胞随后反馈到FRC的结果，都是未知的，其驱动分子机制也是未知的。此外，在免疫应答的背景下，T细胞通常在与FRC网络直接接触时被树突状细胞（DC）激活，因此FRC对激活的T细胞的任何作用都是高度相关的。 我们最近的研究表明，FRC可以在T细胞反应的不同阶段获得抑制功能; FRC的这种新认识的功能似乎通过NOS2依赖性机制控制潜在致病性T细胞的扩增。本项目旨在进一步确定淋巴结内活化T细胞和FRC之间相互作用的分子和物理基础。 尽管最近的进展表明，次级淋巴器官的基质决定因素在免疫反应过程中表现出复杂的调节作用，我们的知识的基质生态位，以及它如何影响T细胞免疫和耐受是有限的。 所提出的研究将定义在FRC抑制CD8 T细胞中达到高潮的分子串扰。最后，这些研究将确定FRC向CD4 T细胞呈递淋巴携带抗原的能力。这些研究的结果将阐明淋巴结FRC和新激活的CD8和CD4 T细胞之间的分子和物理相互作用，以及FRC通过从导管系统中采样抗原在淋巴巡逻中的作用，以及炎症对这些过程的影响。 公共卫生相关性：新出现的证据表明，次级淋巴器官的基质决定簇在免疫应答过程中表现出复杂的调节作用。 我们最近描述了一种新的体内激活的T细胞和成纤维细胞网状细胞（FRC）之间的串扰，赋予这些基质细胞的能力，通过调节一氧化氮（NO）的释放来限制激活的T细胞的增殖。本研究的主要目的是进一步阐明FRC-T细胞串扰的分子和物理基础。这项工作可能为开发新的治疗策略以治疗与肆无忌惮的T细胞免疫相关的人类炎症和自身免疫性疾病提供重要见解。

DESCRIPTION (provided by applicant): Fibroblastic reticular cells (FRCs), one of the major populations of non-hematopoietic stromal cells in lymph node (LNs), secrete extracellular matrix components to form a dense reticular network and lymph-draining conduit system. The T cell zone is delineated by FRCs, forming a scaffold to provide essential guidance cues to immune cells. FRCs orchestrate immune cell migration via expression of CCL19 and CCL21, as well as adhesion molecules, integrins, and glycoproteins. Beyond migration, FRCs maintain na¿ve T cell homeostasis and they have the capacity to impose antigen-specific deletional tolerance, with direct presentation of viral and self-peptides to na¿ve CD8+ T cells. The timing of deletional events in these studies, whether an inevitable outcome of an FRC-mediated activation signal to na¿ve T cells, or a result of subsequent feedback to the FRC from the activated T cell, is unknown, as are its driving molecular mechanisms. Additionally, in the context of immune response, T cells are usually activated by dendritic cells (DCs) while in direct contact with the FRC network, therefore any effect of FRCs on activated T cells is highly relevant. Our recent studies suggest that FRCs can acquire suppressive function at different stages in the T cell response; this newly appreciated function of FRCs appears to control the expansion of potentially pathogenic T cells via a NOS2-dependent mechanism. This project aims to further define the molecular and physical basis of the interactions between activated T cells and FRCs within lymph nodes. Despite recent advances indicating that stromal determinants of secondary lymphoid organs exhibit complex regulatory roles during immune responses, our knowledge of the stromal niche and how it impacts T cell immunity and tolerance is limited. The proposed studies will define the molecular crosstalk that culminates in CD8 T cell suppression by FRCs. They will also establish the influence of FRCs on the positioning and motility of activated T cells Finally, these studies will determine the capacity of FRCs to present lymph-borne antigen to CD4 T cells. The results of these studies will elucidate the molecular and physical interactions between lymph node FRCs and newly activated CD8 and CD4 T cells, and the role of FRCs in patrolling the lymph by sampling antigens from the conduit system, and the impact of inflammation on these processes. PUBLIC HEALTH RELEVANCE: Emerging evidence suggests that stromal determinants of secondary lymphoid organs exhibit complex regulatory roles during immune responses. We recently described a novel in vivo cross-talk between activated T cells and fibroblastic reticular cells (FRCs) that endows these stromal cells with the capacity to constrain the proliferation of activated T cells through regulated nitric oxide (NO) release. The over-arching goal of this proposal is to further elucidate the molecular and physical basis of FRC-T cell cross-talk. This work may provide critical insights for the development of new therapeutic strategies to treat human inflammatory and autoimmune diseases associated with unbridled T cell immunity.