FOXP3 is a direct target of miR15a/16 in umbilical cord blood regulatory T cells.
Exact mechanism of action of umbilical cord blood (CB)-derived regulatory T cells (Tregs) in the prevention of GVHD remains unclear. On the basis of selective overexpression of peptidase inhibitor 16 in CB Tregs, we explored the related p53 pathway, which has been shown to negatively regulate miR15a/16 expression. Significantly lower levels of miR15a/16 were observed in CB Tregs when compared with conventional CB T cells (Tcons). In a xenogeneic GVHD mouse model, lower levels of miR15a/16 were also found in Treg recipients, which correlated with a better GVHD score. Forced overexpression of miR15a/16 in CB Tregs led to inhibition of FOXP3 and CTLA4 expression and partial reversal of Treg-mediated suppression in an allogeneic mixed lymphocyte reaction that correlated with the reversal of FOXP3 demethylation in CB Tregs. On the other hand, miR15a/16 knockdown in CB Tcons led to expression of FOXP3 and CTLA4 and suppression of allogeneic lymphocyte proliferation. Using a luciferase-based mutagenesis assay, FOXP3 was determined to be a direct target of miR15a and miR16. We propose that miR15a/16 has an important role in mediating the suppressive function of CB Tregs and these microRNAs may have a 'toggle-switch' function in Treg/Tcon plasticity.
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
X
X
Liu
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
S N
SN
Robinson
Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
T
T
Setoyama
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
S S
SS
Tung
Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
L
L
D'Abundo
Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
M Y
MY
Shah
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
H
H
Yang
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
E
E
Yvon
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
N
N
Shah
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
H
H
Yang
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
M
M
Konopleva
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
G
G
Garcia-Manero
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
I
I
McNiece
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
K
K
Rezvani
1] Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA [2] Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
G A
GA
Calin
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
E J
EJ
Shpall
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
S
S
Parmar
D000818:Animals; D060908:CTLA-4 Antigen / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000276:immunology; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D016158:Genes, p53; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D002352:Carrier Proteins; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006023:Glycoproteins; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; C501293:PI16 protein, human