Early T cell development in the thymus depends on signals from the IL-7 receptor. To determine the nature of these signals, we examined the effects of IL-7 on very early thymocytes obtained from mouse embryos. We observed that pro-T cells at stages I, II and III underwent rapid apoptotic death in culture and that IL-7 protected them from death, whereas beyond these stages IL-7 did not have trophic activities. Cells deprived of IL-7 underwent death by mechanisms independent of p53 and fas pathways; caspase inhibitors blocked DNA fragmentation but did not maintain cell viability. The trophic activity of IL-7 was attributable in part to sustaining a favorable bcl-2/bax ratio, whereas bcl-x1, bcl-w and bad were not detectable in these cells. Emigration of cells from the thymus was examined using a new method for culturing the mouse embryonic thymus and collecting cells that emigrated from it. Tap1-/- thymuses were used to synchronize positive selection. Within 24 hr following positive selection, T cells expressing a mature phenotype emigrated from the thymus. These emigrants unexpectedly expressed CTLA-4, which normally represses T cell function. Although thymic emigrants tested in vitro recognized alloantigens presented on dendritic cells and proliferated, in vivo they did not induc acute graft-versus-host disease, suggesting that CTLA-4 or some other mechanism suppresses self reactivity of emigrants.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009287-13
Application #
6161065
Study Section
Special Emphasis Panel (LMI)
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
1997
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Wuest, Thomas Y; Willette-Brown, Jami; Durum, Scott K et al. (2008) The influence of IL-2 family cytokines on activation and function of naturally occurring regulatory T cells. J Leukoc Biol 84:973-80
Li, Wen Qing; Jiang, Qiong; Aleem, Eiman et al. (2006) IL-7 promotes T cell proliferation through destabilization of p27Kip1. J Exp Med 203:573-82
Kittipatarin, C; Li, W Q; Bulavin, D V et al. (2006) Cell cycling through Cdc25A: transducer of cytokine proliferative signals. Cell Cycle 5:907-12
Takase, Hiroshi; Yu, Cheng-Rong; Ham, Don-Il et al. (2006) Inflammatory processes triggered by TCR engagement or by local cytokine expression: differences in profiles of gene expression and infiltrating cell populations. J Leukoc Biol 80:538-45
Yao, Zhengju; Cui, Yongzhi; Watford, Wendy T et al. (2006) Stat5a/b are essential for normal lymphoid development and differentiation. Proc Natl Acad Sci U S A 103:1000-5
Khaled, Annette R; Bulavin, Dmitry V; Kittipatarin, Christina et al. (2005) Cytokine-driven cell cycling is mediated through Cdc25A. J Cell Biol 169:755-63
Leviton, Alan; Dammann, Olaf; Durum, Scott K (2005) The adaptive immune response in neonatal cerebral white matter damage. Ann Neurol 58:821-8
Jiang, Q; Li, W-Q; Aiello, F B et al. (2005) Retroviral transduction of IL-7Ralpha into IL-7Ralpha-/- bone marrow progenitors: correction of lymphoid deficiency and induction of neutrophilia. Gene Ther 12:1761-8
Jiang, Qiong; Li, Wen Qing; Hofmeister, Robert R et al. (2004) Distinct regions of the interleukin-7 receptor regulate different Bcl2 family members. Mol Cell Biol 24:6501-13
Ashktorab, H; Frank, S; Khaled, A R et al. (2004) Bax translocation and mitochondrial fragmentation induced by Helicobacter pylori. Gut 53:805-13

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