Human Lymphoid Tissue Inducers

描述（由申请人提供）：类造血组织诱导（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细胞最初被鉴定为启动次级淋巴器官（包括淋巴结和肠派尔集合淋巴结）的胚胎形成的必需细胞。这种独特的细胞谱系在成人中持续存在，并且似乎在炎症反应后淋巴器官的稳态中发挥关键作用。LTi细胞还参与慢性炎症部位三级淋巴聚集体的形成，并且可能对于控制树突状细胞增殖至关重要。LTi细胞极其罕见，通常在成年小鼠脾脏中少于0.5%，使得对其功能的研究极其困难。关于人类的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的纯群体严重阻碍了对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LTi，并鉴定了允许LTi响应于细胞因子信号而存活、扩增和分化的培养条件。培养的、假定的人LTi细胞通过诱导光敏素（LT）-γ和CD 30配体（淋巴稳态和免疫记忆所需的关键细胞因子）来响应IL-7。IL 7还诱导IL 17 A和RORc，这涉及具有与小鼠LTi细胞相似的基因表达谱的成人LTi细胞的扩增。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细胞响应细胞因子的基因表达模式，并用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.