N-Ras or K-Ras inhibition increases the number and enhances the function of Foxp3 regulatory T cells
✍ Scribed by Adi Mor; Gad Keren; Yoel Kloog; Jacob George
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 365 KB
- Volume
- 38
- Category
- Article
- ISSN
- 0014-2980
No coin nor oath required. For personal study only.
✦ Synopsis
Abstract
Naturally occurring regulatory T cells (Treg) driven by their transcriptional controller Foxp3 are compromised in immune‐mediated disorders and confer protection when adoptively transferred. We examined the Ras‐inhibitory effect on functional determinants of Treg in vivo and in vitro. Ras was inhibited in Jurkat T cells by transfection with a dominant‐negative form of Ras, or by shRNA for N‐Ras, K‐Ras, and H‐Ras, or by farnesylthiosalycylic acid, a small‐molecule inhibitor. Except for H‐Ras transduction with shRNA, each inhibitory mode increased expression of Foxp3 and nuclear factor of activated T cell proteins, and surface expression of CD25. Ras inhibition in PBMC and spleen‐derived lymphocytes reproduced these findings. The heightened Foxp3 expression reflected both increased basal cellular protein and peripheral conversion of non‐Treg to Treg. Ras inhibition enhanced Treg‐induced suppression; thus, when adoptively transferred to mice, Ras‐inhibited Treg reduced the incidence of diabetes. Inhibition of Foxp3 by respective siRNA reversed the enhancement. Thus, inhibition of the N‐ or K‐Ras isoform triggers an anti‐inflammatory effect by up‐regulating, via Foxp3 elevation, the numbers and functional suppressive properties of Treg.