title: A dose effect of IL-7 on thymocyte development.
abstract: To study interleukin-7 (IL-7) in early thymocyte development, we generated mice transgenic (Tg) for the IL-7 gene under control of the lck proximal promoter. Founder line TgA, with the lowest level of IL-7 overexpression, showed enhanced alphabeta T-cell development. In contrast, in the highest overexpressing founder line, TgB, alphabeta T-cell development was disturbed with a block at the earliest intrathymic precursor stage. This was due to decreased progenitor proliferation as assessed by Ki-67 staining and in vivo bromodeoxyuridine (BrdU) incorporation. Bcl-2 was up-regulated in T-cell-committed progenitors in all Tg lines, and accounted for greater numbers of double positive (DP), CD4 single positive (SP), and CD8SP thymocytes in TgA mice where, in contrast to TgB mice, thymocyte progenitor proliferation was normal. Mixed marrow chimeras using TgB(+) and congenic mice as donors, and experiments using anti-IL-7 monoclonal antibody (MAb) in vivo, confirmed the role of IL-7 protein in the observed TgB phenotype. In conclusion, at low Tg overexpression, IL-7 enhanced alphabeta T-cell development by increasing thymocyte progenitor survival, while at high overexpression IL-7 reduces their proliferation, inducing a dramatic block in DP production. These results show for the first time in vivo a dose effect of IL-7 on alphabeta T-cell development and have implications for IL-7 in the clinical setting.
authors.affiliation: Experimental Immunology Branch, National Institutes of Health, 10 Center Drive, Bldg 10 Rm 4B36, Bethesda, MD 20892-1360, USA.
authors.forename: Nahed
authors.initials: N
authors.lastname: El Kassar
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Lucas
authors.forename: David B
authors.initials: DB
authors.lastname: Klug
authors.forename: Monica
authors.initials: M
authors.lastname: Zamisch
authors.forename: Melinda
authors.initials: M
authors.lastname: Merchant
authors.forename: Catherine V
authors.initials: CV
authors.lastname: Bare
authors.forename: Baishakhi
authors.initials: B
authors.lastname: Choudhury
authors.forename: Susan O
authors.initials: SO
authors.lastname: Sharrow
authors.forename: Ellen
authors.initials: E
authors.lastname: Richie
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Mackall
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gress
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology; D002455:Cell Division / Q000276:immunology; D018507:Gene Expression Regulation, Developmental / Q000276:immunology*; D015851:Interleukin-7 / Q000235:genetics*; D007694:Killer Cells, Natural / Q000166:cytology / Q000502:physiology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology* / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D015851:Interleukin-7; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D017493:Leukocyte Common Antigens