1. PTEN is required for human Treg suppression of costimulation in vitro.
- Author
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Lam AJ, Haque M, Ward-Hartstonge KA, Uday P, Wardell CM, Gillies JK, Speck M, Mojibian M, Klein Geltink RI, and Levings MK
- Subjects
- Forkhead Transcription Factors metabolism, Humans, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Autoimmune Diseases, PTEN Phosphohydrolase genetics, PTEN Phosphohydrolase metabolism, T-Lymphocytes, Regulatory
- Abstract
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., (© 2022 Wiley-VCH GmbH.)
- Published
- 2022
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