Inhibition of FOXP3/NFAT Interaction Enhances T Cell Function after TCR Stimulation

• Published in: The Journal of immunology (1950) Vol. 195; no. 7; pp. 3180 - 3189
• Main Authors: Lozano, Teresa, Villanueva, Lorea, Durántez, Maika, Gorraiz, Marta, Ruiz, Marta, Belsúe, Virginia, Riezu-Boj, José I, Hervás-Stubbs, Sandra, Oyarzábal, Julen, Bandukwala, Hozefa, Lourenço, Ana R, Coffer, Paul J, Sarobe, Pablo, Prieto, Jesús, Casares, Noelia, Lasarte, Juan J
• Format: Journal Article
• Language: English
• Published: United States 01-10-2015
• Subjects: Animals; Antineoplastic Agents - pharmacology; CD40 Ligand - biosynthesis; CD40 Ligand - genetics; Cell Proliferation - genetics; CTLA-4 Antigen - biosynthesis; Female; Forkhead Transcription Factors - antagonists & inhibitors; Forkhead Transcription Factors - metabolism; Humans; Immunotherapy; Interferon-gamma - biosynthesis; Interleukin-17 - biosynthesis; Interleukin-17 - genetics; Interleukin-2 - biosynthesis; Interleukin-2 Receptor alpha Subunit - biosynthesis; Interleukin-6 - biosynthesis; Jurkat Cells; Lymphocyte Activation - immunology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms - therapy; NFATC Transcription Factors - antagonists & inhibitors; NFATC Transcription Factors - metabolism; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Ovalbumin - immunology; Peptide Fragments - pharmacology; Phenylurea Compounds - pharmacology; Promoter Regions, Genetic - genetics; Receptors, Antigen, T-Cell - immunology; T-Lymphocytes, Regulatory - immunology; Transforming Growth Factor beta - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1402997

Regulatory T cell (Treg) activity is modulated by a cooperative complex between the transcription factor NFAT and FOXP3, a lineage specification factor for Tregs. FOXP3/NFAT interaction is required to repress expression of IL-2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function to Tregs. However, FOXP3 is expressed transiently in conventional CD4(+) T cells upon TCR stimulation and may lead to T cell hyporesponsiveness. We found that a short synthetic peptide able to inhibit FOXP3/NFAT interaction impaired suppressor activity of conventional Tregs in vitro. Specific inhibition of FOXP3/NFAT interaction with this inhibitory peptide revealed that FOXP3 downregulates NFAT-driven promoter activity of CD40L and IL-17. Inhibition of FOXP3/NFAT interaction upregulated CD40L expression on effector T cells and enhanced T cell proliferation and IL-2, IFN-γ, IL-6, or IL-17 production in response to TCR stimulation. The inhibitory peptide impaired effector T cell conversion into induced Tregs in the presence of TGF-β. Moreover, in vivo peptide administration showed antitumor efficacy in mice bearing Hepa129 or TC1 tumor cells when combined with sorafenib or with an antitumor vaccine, respectively. Our results suggest that inhibition of NFAT/FOXP3 interaction might improve antitumor immunotherapies.