UBD, a downstream element of FOXP3, allows the identification of LGALS3, a new marker of human regulatory T cells

Here, we report the identification of the ubiquitin-like gene UBD as a downstream element of FOXP3 in human activated regulatory CD4+CD25hi T cells (Treg). Retroviral transduction of UBD in human allo-reactive effector CD4+ T helper (Th) cells upregulates CD25 and mediates downregulation of IL4 and IL5 expression similar to overexpression of FOXP3. Moreover, UBD impairs Th cell proliferation without upregulation of FOXP3 and impairs calcium mobilization. In the presence of ionomycin, overexpression of UBD in Th cells leads to the induction of IL1R2 that resemble FOXP3-transduced Th cells and naturally derived Treg cells. A comparison of the transcriptome of FOXP3- and UBD-transduced Th cells with Treg cells allowed the identification of the gene LGALS3. However, high levels of LGALS3 protein expression were observed only in human CD4+CD25hi derived Treg cells and FOXP3-transduced Th cells, whereas little was induced in UBD-transduced Th cells. Thus, UBD contributes to the anergic phenotype of human regulatory T cells and acts downstream in FOXP3 induced regulatory signaling pathways, including regulation of LGALS3 expression. High levels of LGALS3 expression represent a FOXP3-signature of human antigen-stimulated CD4+CD25hi derived regulatory T cells.