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.
Ocklenburg
Frank
F
Junior Research Group for Xenotransplantation, Department of Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.
Moharregh-Khiabani
Darius
D
Geffers
Robert
R
Janke
Viktoria
V
Pfoertner
Susanne
S
Garritsen
Henk
H
Groebe
Lothar
L
Klempnauer
Juergen
J
Dittmar
Kurt E J
KE
Weiss
Siegfried
S
Buer
Jan
J
Probst-Kepper
Michael
M
D015415:Biomarkers / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D037502:Galectin 3 / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D015848:Interleukin-5 / Q000276:immunology / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis; D053574:Receptors, Interleukin-1 Type II; D015375:Receptors, Interleukin-2 / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D014161:Transduction, Genetic; D014452:Ubiquitins / Q000235:genetics / Q000276:immunology*
D015415:Biomarkers; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D037502:Galectin 3; C508592:IL1R2 protein, human; D015848:Interleukin-5; D007476:Ionophores; D017472:Receptors, Interleukin-1; D053574:Receptors, Interleukin-1 Type II; D015375:Receptors, Interleukin-2; C109184:UBD protein, human; D014452:Ubiquitins; D015847:Interleukin-4; D015759:Ionomycin; D002118:Calcium