A peptide inhibitor of FOXP3 impairs regulatory T cell activity and improves vaccine efficacy in mice.

Abstract

Immunosuppressive activity of regulatory T cells (Treg) may contribute to the progression of cancer or infectious diseases by preventing the induction of specific immune responses. Using a phage-displayed random peptide library, we identified a 15-mer synthetic peptide, P60, able to bind to forkhead/winged helix transcription factor 3 (FOXP3), a factor required for development and function of Treg. P60 enters the cells, inhibits FOXP3 nuclear translocation, and reduces its ability to suppress the transcription factors NF-κB and NFAT. In vitro, P60 inhibited murine and human-derived Treg and improved effector T cell stimulation. P60 administration to newborn mice induced a lymphoproliferative autoimmune syndrome resembling the reported pathology in scurfy mice lacking functional Foxp3. However, P60 did not cause toxic effects in adult mice and, when given to BALB/c mice immunized with the cytotoxic T cell epitope AH1 from CT26 tumor cells, it induced protection against tumor implantation. Similarly, P60 improved the antiviral efficacy of a recombinant adenovirus expressing NS3 protein from hepatitis C virus. Functional inhibition of Treg by the FOXP3-inhibitory peptide P60 constitutes a strategy to enhance antitumor and antiviral immunotherapies.

• Authors: Noelia Casares, Francesc Rudilla, Laura Arribillaga, Diana Llopiz, José Ignacio Riezu-Boj, Teresa Lozano, Jacinto López-Sagaseta, Laura Guembe, Pablo Sarobe, Jesús Prieto, Francisco Borrás-Cuesta, Juan José Lasarte
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 185 Issue 9 Pg. 5150-9 (Nov 01 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20870946 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Forkhead Transcription Factors
• Foxp3 protein, mouse
• Peptide Library
• Peptides
• Vaccines

Topics

• Animals
• Female
• Forkhead Transcription Factors (antagonists & inhibitors)
• Humans
• Immunohistochemistry
• Mice
• Mice, Inbred BALB C
• Mice, Inbred ICR
• Microscopy, Confocal
• Peptide Library
• Peptides (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• T-Lymphocytes, Regulatory (drug effects, immunology, metabolism)
• Transfection
• Vaccines (immunology)