Regulatory transplantation tolerance and stemness: Evidence that Foxp3 may play a regulatory role in SOCS-3 gene transcription

Immune self-tolerance is controlled by a subset of T lymphocytes that are regulatory (Treg) and epigenetically programmed to suppress autoreactive immune effector cells in vivo. Treg require expression of Foxp3, a transcription factor that not only represses the interleukin-2 gene promoter, but also sequesters key mediators of T-cell signal transduction by complexing with cytoplasmic NFAT and NF kappa B. We have discovered that expression of Foxp3 is linked to two stem cell-related factors, namely leukemia inhibitory factor (LIF) and axotrophin. Because both LIF and axotrophin each influence Foxp3, we now ask if reciprocal cross-talk occurs; for example, does Foxp3 in turn influence LIF and/or axotrophin? We compared the effect of wt-Foxp3 versus mutant Delta E251-Foxp3, which lacks transcriptional activity, on transcript levels of axotrophin, LIF, and suppressor of cytokine signaling-3 (SOCS-3; a feedback inhibitor of LIF) in the Jurkat human T-cell line. Unexpectedly, a 50-fold increase in SOCS-3 transcripts occurred in the Delta E251-Foxp3 cells, coincident with a dramatic decrease in LIF transcription. This implies that, either directly or indirectly, transcription of SOCS-3 is negatively regulated by wt-Foxp3. Suppression of SOCS-3 by Foxp3 would support a model wherein Foxp3 promotes LIF signaling in Treg and is further evidence of reciprocity between Foxp3, LIF, and axotrophin.