Human Lymphoid Tissue Inducers

描述（由申请人提供）：淋巴组织诱导剂（LTi）细胞是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剂。LTi细胞最初被认为是启动次级淋巴器官（包括淋巴结和肠道Peyer’s patches）胚胎形成的重要细胞。这种独特的细胞谱系在成人中持续存在，似乎在炎症反应后淋巴器官的稳态中起着关键作用。LTi细胞也与慢性炎症部位的三级淋巴样聚集体的形成有关，并且可能对控制树突状细胞增殖至关重要。LTi细胞非常罕见，在成年小鼠脾脏中通常不到0.5%的细胞，这使得对其功能的研究非常困难。人类LTi谱系及其在免疫功能中的作用几乎一无所知。缺乏培养系统来培养这些细胞在纯群体中严重阻碍了对LTi细胞功能的研究。我们最近使用高速细胞分选从外周血中分离出人类LTi，并确定了允许LTi存活、扩增和分化的培养条件，以响应细胞因子信号。培养的，假定的人LTi细胞通过诱导淋巴素(LT)-¿和CD30配体，淋巴稳态和免疫记忆所需的关键细胞因子，对IL-7作出反应。IL7还能诱导IL17A和RORc，暗示成人LTi细胞的扩增，其基因表达谱与小鼠LTi细胞相似。这一发现将有助于评估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，我们将表征人类LTi细胞对细胞因子的基因表达模式，并通过纯细胞群确定其免疫调节特性。

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.