A dose effect of IL-7 on thymocyte development

• Published in: Blood 2004-09, Vol.104 (5), p.1419-1427
• Main Authors: El Kassar, Nahed, Lucas, Philip J., Klug, David B., Zamisch, Monica, Merchant, Melinda, Bare, Catherine V., Choudhury, Baishakhi, Sharrow, Susan O., Richie, Ellen, Mackall, Crystal L., Gress, Ronald E.
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes - cytology; B-Lymphocytes - physiology; Biological and medical sciences; Cell Division - immunology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation, Developmental - immunology; Immunobiology; Interleukin-7 - genetics; Killer Cells, Natural - cytology; Killer Cells, Natural - physiology; Leukocyte Common Antigens - metabolism; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - genetics; Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Promoter Regions, Genetic; Proto-Oncogene Proteins c-bcl-2 - metabolism; Receptors, Antigen, T-Cell, alpha-beta - metabolism; RNA, Messenger - metabolism; Stem Cells - cytology; Stem Cells - physiology; T-Lymphocytes - cytology; T-Lymphocytes - physiology; Thymus Gland - cytology; Thymus Gland - embryology; Thymus Gland - physiology; Up-Regulation - immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-01-0201

To study interleukin-7 (IL-7) in early thymocyte development, we generated mice transgenic (Tg) for the IL-7 gene under control of thelckproximal promoter. Founder line TgA, with the lowest level of IL-7 overexpression, showed enhanced αβ T-cell development. In contrast, in the highest overexpressing founder line, TgB, αβ 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 αβ 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 αβ T-cell development and have implications for IL-7 in the clinical setting.