Human Lymphoid Tissue Inducers

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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.