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Updated: May 1, 2026
In Vivo Augmentation of Gut-Homing Regulatory T Cell Induction
Published on: January 22, 2020
FOXP3 is a direct target of miR15a/16 in umbilical cord blood regulatory T cells
X Liu1, S N Robinson1, T Setoyama2
1Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Abstract:
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.
Insights
MicroRNAs miR15a/16 regulate the function of umbilical cord blood regulatory T cells (Tregs) in preventing graft-versus-host disease (GVHD). Lower miR15a/16 levels enhance Treg function, suggesting a role in GVHD prevention.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- The precise mechanism by which umbilical cord blood (CB)-derived regulatory T cells (Tregs) prevent graft-versus-host disease (GVHD) is not fully understood.
- Peptidase inhibitor 16 is selectively overexpressed in CB Tregs, implicating the p53 pathway and microRNA regulation.
Purpose of the Study:
- To investigate the role of miR15a/16 in the function of CB Tregs and their potential involvement in GVHD prevention.
- To explore the regulatory relationship between miR15a/16, p53 pathway, and Treg/Tcon plasticity.
Main Methods:
- Comparative analysis of miR15a/16 levels in CB Tregs versus conventional T cells (Tcons).
- Assessment of miR15a/16 levels and GVHD scores in a xenogeneic GVHD mouse model.
- Functional assays involving forced miR15a/16 overexpression in Tregs and knockdown in Tcons.
- Luciferase-based mutagenesis assay to identify direct targets of miR15a/16.
Main Results:
- CB Tregs exhibited significantly lower levels of miR15a/16 compared to CB Tcons.
- Lower miR15a/16 levels in Treg recipients correlated with improved GVHD scores in a mouse model.
- Modulation of miR15a/16 levels affected FOXP3 and CTLA4 expression and Treg-mediated suppression.
- FOXP3 was identified as a direct target of miR15a and miR16.
Conclusions:
- miR15a/16 plays a crucial role in mediating the suppressive function of CB Tregs.
- These microRNAs may act as a 'toggle-switch' influencing the plasticity between Treg and Tcon phenotypes.
- Understanding miR15a/16 regulation offers potential therapeutic strategies for GVHD prevention.
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