Feedback loops comprise key mechanisms by which signal inhibition and propagation is controlled within cells. Signaling through a receptor may lead to signal inhibition via receptor internalization, induction of inhibitory phosphatases or transcriptional changes in receptor or regulator expression. Likewise, positive signaling feedback can be generated by inducing transcription of the receptor or its positive regulators or by autocrine secretion of a stimulatory ligand. Signaling feedback control is an important regulatory process in IL-7 signaling that allows avoidance of pathway saturation, establishment of signaling thresholds and fine tuning of the signal at an optimal level for cell survival. Understanding the balance of positive and negative feedback loops will be essential for a complete understanding of cytokine responses.
Negative feedback loops are particularly important in regulation of IL-7Rα expression. Receptor ligation leads to endocytic loss of the receptor from the surface, contributing to signal attenuation. In addition to receptor loss from internalization, several γc cytokines, including IL-7, activate both negative and positive feedback loops to modulate receptor mRNA expression. In CD8+
T cells, downregulation is mediated by the transcriptional repressor Gfi1, which is upregulated upon IL-7 signaling, as well as signaling by other interleukin family members30
. A second transcriptionally mediated negative feedback loop involves upregulation of SOCS1 expression upon cytokine signaling (). SOCS1 can directly inhibit Jaks by acting as a pseudosubstrate through its kinase inhibitory region, as well as by ubiquitin-mediated degradation of the signaling complex itself23
. In addition, cytokine-independent regulation of SOCS1 also plays critical roles in regulating signaling by IL-7 and other γc cytokines throughout development. For example, SOCS1 is expressed at high levels in DP cells during thymic development to prevent IL-7 signaling and possible aberrant positive selection31
. SOCS1 knockout mice show spontaneous activation of lymphocytes even in a pathogen free environment32
. A number of negative regulators of the Stats have also been identified such as the PIAS family of proteins33
. However, the relative contribution of these mechanisms of signal feedback inhibition to the overall control of IL-7 signal attenuation is yet to be elucidated.
Influence of Feedback Control on Signaling
IL-7 signaling also elicits positive feedback loops which contribute to signal amplification and sharp response thresholds. In developing B cells, IL-7 signaling causes upregulation of the transcription factors EBF and E2A, which in turn upregulate IL-7Rα, leading to a self-sustaining positive feedback loop34
. Feedback loops in IL-7 signaling play a critical role in B cell development by maintaining B cell lineage commitment among differentiating common lymphoid progenitors. In addition, sustained IL-7 signaling is necessary for survival of pro-B cell35
. EBF and E2A coordinately regulate the initiation of the B cell gene expression program as well as rearrangement of the immunoglobulin heavy chain loci33
. The signal feedback loops between these proteins ensure normal development of B cell precursors through various checkpoints in B cell development.
It was recently shown that in macrophages, Tat protein produced by the human immunodeficiency virus (HIV) can cause upregulation of IL-7Rα and increase IL-7 signaling. Increased signaling in turn promotes early infection events including viral entry, and ultimately efficient viral production36
. Interestingly, the effect of HIV Tat protein on CD8+
T cells was the opposite of that seen in macrophages, where it instead decreased IL-7Rα expression, inhibiting cell survival signaling37
. A detailed analysis of the complex, cell-specific feedback mechanisms will help better understanding how the IL-7 signaling network is exploited by pathogens.