Interlinking interleukin-7

Abstract

The signaling processes that maintain the homeostatic proliferation of peripheral T-cells and result in their self-renewal largely remain to be elucidated. Much focus has been placed on the anti-apoptotic function of the cytokine, interleukin-7 (IL-7), during T-cell development. But a more critical role has been ascribed to IL-7 as a mediator of peripheral T-cell maintenance. The biological effects responsive to IL-7 signaling are transduced through only a few well-known pathways. In this review we will focus on the signals transduced by IL-7 and similar cytokines, examining how proliferative signals originate from cytokine receptors, are amplified and eventually alter gene expression. In this regard we will highlight the crosstalk between pathways that promote survival, drive cell cycle progression and most importantly provide the needed energy to sustain these critical cellular activities. Though this review showcases much of what has been learned about IL-7 proliferative signaling, it also reveals the significant gaps in our knowledge about cytokine signaling in the very relevant context of peripheral T-cell homeostasis.

Figure 1. IL-7 Signaling Pathways that Drive Proliferation, Survival and Metabolism

Binding of IL-7 causes dimerization of its receptor chains and activation of the receptor–associated JAK1 and JAK3. JAKs in turn phosphorylate receptor docking sites for STAT5, leading to the transcription factor’s phosphorylation, dimerization and nuclear translocation, perhaps inducing novel gene products that promote survival (X, Y). Other signaling pathways that may stem directly or indirectly (X) from the IL-7 receptor include the PI3K/AKT pathway which inhibits apoptotic proteins and the cell cycle inhibitor, p27^kip1, and promotes glucose uptake through the glucose transporter, GLUT1. Unknown signaling pathways (X) also regulate the activity of the stress kinase, p38 MAPK. Down-regulation of p38 MAPK leads to the stable expression of Cdc25A, the activator of cdk/cyclin complexes that promotes proliferation and gene expression likely through activation of the E2F transcription factors. Expression of the survival protein, BCL-2, is up-regulated by IL-7, perhaps through STAT5 activity, but more likely through unknown transcriptional activity (Z). T-cell proliferation in response to IL-7 thus requires signals that drive cell cycle progression but also provide survival signals that prevent apoptosis and produce energy to support cell division.