PTEN is required for human Treg suppression of costimulation in vitro

Regulatory T‐cell (Treg) therapy is under clinical investigation for the treatment of transplant rejection, autoimmune disease, and graft‐versus‐host disease. With the advent of genome editing, attention has turned to reinforcing Treg function for therapeutic benefit. A hallmark of Tregs is dampened...

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Published in:European journal of immunology 2022-09, Vol.52 (9), p.1482-1497
Main Authors: Lam, Avery J., Haque, Manjurul, Ward‐Hartstonge, Kirsten A., Uday, Prakruti, Wardell, Christine M., Gillies, Jana K., Speck, Madeleine, Mojibian, Majid, Klein Geltink, Ramon I., Levings, Megan K.
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
Antigen-presenting cells
Antigens
Autoimmune diseases
CRISPR
CRISPR–Cas9
Foxp3 protein
Genome editing
Genomes
Glycolysis
Graft rejection
immune regulation
Lymphocytes T
Phenotypes
PI3K‐AKT
PTEN
PTEN protein
regulatory T cells
Signal transduction
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Summary:Regulatory T‐cell (Treg) therapy is under clinical investigation for the treatment of transplant rejection, autoimmune disease, and graft‐versus‐host disease. With the advent of genome editing, attention has turned to reinforcing Treg function for therapeutic benefit. A hallmark of Tregs is dampened activation of PI3K‐AKT signaling, of which PTEN is a major negative regulator. Loss‐of‐function studies of PTEN, however, have not conclusively shown a requirement for PTEN in upholding Treg function and stability. Using CRISPR‐based genome editing in human Tregs, we show that PTEN ablation does not cause a global defect in Treg function and stability; rather, it selectively blocks their ability to suppress antigen‐presenting cells. PTEN‐KO Tregs exhibit elevated glycolytic activity, upregulate FOXP3, maintain a Treg phenotype, and have no discernible defects in lineage stability. Functionally, PTEN is dispensable for human Treg‐mediated inhibition of T‐cell activity in vitro and in vivo but is required for suppression of costimulatory molecule expression by antigen‐presenting cells. These data are the first to define a role for a signaling pathway in controlling a subset of human Treg activity. Moreover, they point to the functional necessity of PTEN‐regulated PI3K‐AKT activity for optimal human Treg function. PTEN ablation in human Tregs and consequent increased PI3K‐AKT activity does not cause a global defect in Treg function and stability, in contrast to mice. Rather, it selectively blocks their ability to suppress antigen‐presenting cells.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.202249888