Human Lymphoid Tissue Inducers

描述(申请人提供)：淋巴组织诱导物(LTI)细胞代表一种罕见的造血细胞谱系，已成为淋巴组织稳态的关键调节因子。LTI细胞最初被认为是启动次级淋巴器官胚胎形成的基本细胞，包括淋巴结和肠道Peyer‘s斑块。这种独特的细胞谱系在成人中持续存在，并似乎在炎症反应后淋巴器官的动态平衡中发挥关键作用。LTI细胞也与慢性炎症部位第三级淋巴聚集体的形成有关，并且可能是控制树突状细胞增殖的关键。LTI细胞极其罕见，在成年小鼠的脾中通常不到0.5%的细胞，这使得对其功能的研究变得极其困难。几乎对人类的LTI谱系及其在免疫功能中的作用知之甚少。缺乏在纯群体中培养这些细胞的培养系统，严重阻碍了对LTI细胞功能的研究。最近，我们使用高速细胞分选从外周血中分离出人LTI，并确定了允许LTI在细胞因子信号作用下存活、扩增和分化的培养条件。培养的人类LTI细胞通过诱导淋巴毒素(LT)-β和CD30配体对IL-7做出反应，这是淋巴系统稳态和免疫记忆所需的关键细胞因子。IL7还诱导了IL17A和RORC，提示成人LTI细胞具有与小鼠LTI细胞相似的基因表达谱。这一发现将使我们能够评估LTI细胞在免疫反应中的作用，并确定治疗疾病的新策略。为了实现这一目标，我们将表征人LTI细胞对细胞因子的反应基因表达模式，并与纯细胞群体一起确定其免疫调节特性。 公共卫生相关性：我们的研究分离出一种罕见的人类白细胞，其特征可能对调节对病原体的免疫反应很重要。我们已经开发出一种允许这些细胞生长的培养方法，这将有助于我们识别这些细胞可能独有的基因，并为研究人类感染提供这种细胞的分子身份。

DESCRIPTION (provided by applicant): Lymphoid tissue inducer (LTi) cells represent a rare hematopoietic cell lineage that has emerged as a key regulator of lymphoid tissue homeostasis. LTi cells were originally identified as an essential cell that initiates the embryonic formation of secondary lymphoid organs, including lymph nodes and intestinal Peyer's patches. This distinct lineage of cells persists in the adult and appears to play a critical role in the homeostasis of lymphoid organs following inflammatory responses. LTi cells are also implicated in formation of tertiary lymphoid aggregates at sites of chronic inflammation, and may be critical for controlling dendritic cell proliferation. LTi cells are extremely rare, typically less than 0.5% cells in the adult mouse spleen, making investigation into their function extremely difficult. Almost nothing is known about the LTi lineage in humans and their role in immune function. The lack of culture systems to grow these cells in pure populations has severely hampered investigations into the function of LTi cells. We have recently isolated human LTi from peripheral blood using high speed cell sorting, and identified culture conditions that allow LTi to survive, expand and differentiate in response to cytokine signals. The cultured, putative human LTi cells respond to IL-7 by induction of lymphotoxin (LT)-¿ and CD30 ligand, key cytokines required for lymphoid homeostasis and immune memory. IL7 also induced IL17A and RORc implicating expansion of adult human LTi cells with gene expression profile similar to mouse LTi cells. This discovery will allow assessment of the role of LTi cells in immune responses and identify new strategies in treating disease. To accomplish this goal we will characterize the gene expression patterns of human LTi cells in response to cytokines, and with pure population of cells determine their immune regulatory properties. PUBLIC HEALTH RELEVANCE: Our research has isolated a rare human white blood cell with characteristics that may be important in regulating immune responses to pathogens. We have developed a culture method that allows these cells to grow, which will aid us in identifying genes that may be unique to these cells, and provide molecular identity of this cell to study in human infections.