title: Removal of myeloid cytokines from the cellular environment enhances T-cell development in vitro.
abstract: The majority of T-cell development occurs in the thymus. Thymic epithelial cells are specialized cells that express NOTCH ligands and secrete specific cytokines required for normal T-cell lymphopoiesis. It has been demonstrated that OP9 cells derived from macrophage colony-stimulating factor (M-CSF)-deficient mice can support T-cell development when transduced with a NOTCH ligand, Delta-like 1 (Dll1). In this report, we have tested CSF-deficient mouse fibroblasts transduced with Dll1 for their ability to support T-cell differentiation. The data provided here demonstrate that CSF-deficient fibroblasts expressing DLL1 can support T-cell development. Indeed, co-cultures with these fibroblasts produced more T-cell progenitors compared with OP9-DL1 cultures. Addition of myeloid cytokines to OP9-DL1 co-cultures significantly inhibited T-cell development while CSF-deficient DLL1(+) fibroblasts retained partial T-cell differentiation. Taken together, these data imply that their lack of myeloid cytokines allows DLL1(+) fibroblasts to more efficiently generate T-cells. Development of this fibroblast system suggests that there is potential for generating human T-cell precursors via co-culture with human fibroblasts expressing DLL1 or DLL4. These T-cell precursors could be used for treating immunodeficient patients.
authors.affiliation: Haematology and Leukaemia Unit, St Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria 3065, Australia.
authors.forename: Monique F M A
authors.initials: MF
authors.lastname: Smeets
authors.forename: Charley
authors.initials: C
authors.lastname: Mackenzie-Kludas
authors.forename: Mahmood
authors.initials: M
authors.lastname: Mohtashami
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Zhang
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Zúñiga-Pflücker
authors.forename: David J
authors.initials: DJ
authors.lastname: Izon
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D002460:Cell Line; D060833:Cellular Microenvironment; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D005347:Fibroblasts / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000276:immunology / Q000628:therapy*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*
chemical_list: D002135:Calcium-Binding Proteins; D016207:Cytokines; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051880:Receptors, Notch
keywords: Delta-like 1; NOTCH ligand; T-cell development; fibroblast; in vitro; myeloid cytokine