title: N-Ras or K-Ras inhibition increases the number and enhances the function of Foxp3 regulatory T cells.
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.
authors.affiliation: Cardiovascular Research Center, Department of Cardiology, Tel Aviv Sourasky Medical Center, Affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Mor
authors.forename: Gad
authors.initials: G
authors.lastname: Keren
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
authors.forename: Jacob
authors.initials: J
authors.lastname: George
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D018920:Coculture Techniques; D003920:Diabetes Mellitus / Q000276:immunology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005204:Farnesol / Q000031:analogs & derivatives / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D050778:NFATC Transcription Factors / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012459:Salicylates / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D014162:Transfection; D015854:Up-Regulation / Q000276:immunology
chemical_list: D004791:Enzyme Inhibitors; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D050778:NFATC Transcription Factors; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D016283:Proto-Oncogene Proteins p21(ras)