IL-7 signaling and CD127 receptor regulation in the control of T cell homeostasis

Abstract

After their development in the thymus, mature T cells are maintained in the periphery by two sets of survival signals, namely TCR signals from contact with self-peptide/MHC ligands and the cytokine receptor signals from binding IL-7 and IL-15. These signals cooperate to maximize the utility of finite resources to support a diverse pool of mature T cells. It is becoming increasingly clear that multiple mechanisms exist to regulate expression of IL-7R at the transcriptional and post-translational levels. The interplay between TCR signals and IL-7R signals are also important in regulation of IL-7R expression. This review will focus on regulation of T cell homeostasis by IL-7R signaling, with an emphasis on the cross talk between signals from TCR and IL-7R.

Figure 1. Cross-talk between signals from self-pMHC and IL-7

Many transcription factors and molecules downstream of TCR control CD127 expression, either by inducing or inhibiting its transcription. In green; transcription factors inducing CD127 transcription. In red; transcription factors repressing CD127 transcription. TCR signals can also induce formation of lipid rafts, which could recruit and concentrate IL-7R, thereby amplifying its downstream signaling pathway. It is still unclear if IL-7 signaling activates the PI3K signaling pathway in lymphoreplete hosts, but if it were to be true, Foxo1 and Foxp1 could finely regulate CD127 expression downstream of IL-7, allowing a limited IL-7 to support survival of a maximal number of T cells. Whether Gfi-1, GABPα or Ets-1 are are activated downstream of IL-7R or self-pMHC/TCR interactions is still not known, but Gfi-1 expression is induced downstream of strong TCR triggering [79, 80, 106].

Figure 2. IL-7-induced recycling/degradation of CD127

In the absence of IL-7, the ephrins Efnb1 and Efnb2 stabilize CD127 expression at the cell surface. Eventually, CD127 will be internalized. Vps34 activity in the multivesicular bodies will recruit FYVE and GLUE containing proteins that will allow the recycling of a significant proportion of the CD127 chain back to the cell surface. Upon IL-7 binding to the IL-7R, the internalized receptor is targeted to the lysosomal and proeasomal degradation pathways in a Jak3-dependent manner. The Vps34-dependent recycling does not apply to the γ_c chain, which is always degraded by the lysosomal pathway