The Journal of Experimental Medicine
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Published 17 February 2003. doi:10.1084/jem.20021765
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© Rockefeller University Press, 0022-1007/2003/2/475 $5.00
The Journal of Experimental Medicine, Volume 197, Number 4, 475-487

In Vitro Evidence That Cytokine Receptor Signals Are Required for Differentiation of Double Positive Thymocytes into Functionally Mature CD8+ T Cells

Qing Yu, Batu Erman, Avinash Bhandoola, Susan O. Sharrow and Alfred Singer

Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Alfred Singer, Experimental Immunology Branch, National Cancer Institute, Building 10, Room 4B36, Bethesda, MD 20892. Phone: 301-496-5461; Fax: 301-496-0887; E-mail: SingerA{at}nih.gov

CD4+8+ double positive (DP) thymocytes differentiate into CD4+ and CD8+ mature T cells in response to TCR signals. However, TCR signals that are initiated in DP thymocytes are unlikely to persist throughout all subsequent differentiation steps, suggesting that other signals must sustain thymocyte differentiation after TCR signaling has ceased. Using an in vitro experimental system, we now demonstrate that cytokine receptor signals, such as those transduced by IL-7 receptors, are required for differentiation of signaled DP thymocytes into functionally mature CD8+ T cells as they: (a) up-regulate Bcl-2 expression to maintain thymocyte viability; (b) enhance CD4 gene silencing; (c) promote functional maturation;and (d) up-regulate surface expression of glucose transporter molecules, which improve nutrient uptake and increase metabolic activity. IL-7Rs appear to be unique among cytokine receptors in maintaining the viability of newly generated CD4-8+ thymocytes, whereas several different cytokine receptors can provide the trophic/differentiative signals for subsequent CD8+ thymocyte differentiation and maturation. Thus, cytokine receptors provide both survival and trophic/differentiative signals with varying degrees of redundancy that are required for differentiation of signaled DP thymocytes into functionally mature CD8+ T cells.

Key Words: coreceptor reversal • kinetic signaling • positive selection • IL-7


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