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(+)CD25(hi) T cells (T-reg). Retroviral transduction of UBD in human allo-reactive effector CD4(+) T helper (T-h) cells upregulates CD25 and mediates downregulation of IL4 and IL5 expression similar to overexpression of FOXP3. Moreover, UBD impairs T-h cell proliferation without upregulation of FOXP3 and impairs calcium mobilization. In the presence of ionomycin, overexpression of UBD in T-h cells leads to the induction of IL1R2 that resemble FOXP3-transduced T-h cells and naturally derived T-reg cells. A comparison of the transcriptome of FOXP3- and UBD-transduced T-h cells with T-reg cells allowed the identification of the gene LGALS3. However, high levels of LGALS3 protein expression were observed only in human CD4(+)CD25(hi) derived T-reg cells and FOXP3- transduced T-h cells, whereas little was induced in UBD-transduced T-h 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(+)CD25(hi) derived regulatory T cells.