Anergy-derived Treg cell differentiation in the neonatal mouse hepatic microenvironment

Abstract

Abstract The neonatal environment is a natural scenario to study the effects of peripheral self-antigen recognition and induction of immune tolerance within the CD4 T lymphocyte repertoire. Interestingly, we have found that polyclonal Nrp1+ CD73+ anergic conventional CD4 T cells and Foxp3+ regulatory T cells (Tregs) accumulate in the neonatal liver. These observations make the neonatal liver an interesting place to study anergy-derived Foxp3+ Treg cell differentiation. We hypothesize that self-reactive CD4 T cells become anergic in neonates and generate Treg cell progenitors. Furthermore, we predict that unlike secondary lymphoid organs, the neonatal liver microenvironment fails to support anergy maintenance and, therefore, allows anergy-derived Treg cell progenitors to differentiate into Foxp3+Tregs. Accordingly, the objective of this study was to specifically analyze the induction of CD4 T cell anergy and the trans-differentiation of anergic conventional T cells into the Foxp3+ Treg cell lineage within the neonatal liver. We now report that anergic OT-II CD4 T cells partially reverse their anergic phenotype and give rise to Foxp3+Tregs cells within the hepatic environment when transferred into neonatal mice that ubiquitously express an OVA transgene. These findings support the model that a change in the metabolism of anergic CD4 T cells within the neonatal liver leads to cell-cycle progression and chromosomal replication, which then allows for the complete de-methylation of the Foxp3CNS2 locus and differentiation into the Foxp3+ Treg lineage. Future experiments will analyze the importance of enzymes such as DNMT and TET proteins that regulate the epigenetic state of Treg cell progenitors within the anergic cell compartment.