A dose effect of IL-7 on thymocyte development.
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.
El Kassar
Nahed
N
Experimental Immunology Branch, National Institutes of Health, 10 Center Drive, Bldg 10 Rm 4B36, Bethesda, MD 20892-1360, USA.
Lucas
Philip J
PJ
Klug
David B
DB
Zamisch
Monica
M
Merchant
Melinda
M
Bare
Catherine V
CV
Choudhury
Baishakhi
B
Sharrow
Susan O
SO
Richie
Ellen
E
Mackall
Crystal L
CL
Gress
Ronald E
RE
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
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