Inhibition of FOXP3/NFAT Interaction Enhances T Cell Function after TCR Stimulation.
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.
Gene Therapy and Hepatology Division, Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;
Teresa
T
Lozano
Gene Therapy and Hepatology Division, Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;
Lorea
L
Villanueva
Gene Therapy and Hepatology Division, Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;
Maika
M
Durántez
Gene Therapy and Hepatology Division, Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain;
Marta
M
Gorraiz
Gene Therapy and Hepatology Division, Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain;
Marta
M
Ruiz
Gene Therapy and Hepatology Division, Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;
Virginia
V
Belsúe
Gene Therapy and Hepatology Division, Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain;
José I
JI
Riezu-Boj
Gene Therapy and Hepatology Division, Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain;
Sandra
S
Hervás-Stubbs
Small Molecule Discovery Platform, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;
Julen
J
Oyarzábal
Signaling and Gene Expression Division, La Jolla Institute for Allergy and Immunology, San Diego, CA 92037; and.
Hozefa
H
Bandukwala
Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
Ana R
AR
Lourenço
Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
Paul J
PJ
Coffer
Gene Therapy and Hepatology Division, Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain;
Pablo
P
Sarobe
Gene Therapy and Hepatology Division, Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;
Jesús
J
Prieto
Gene Therapy and Hepatology Division, Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain; jjlasarte@unav.es ncasares@unav.es.
Noelia
N
Casares
Gene Therapy and Hepatology Division, Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, 31008 Pamplona, Spain; jjlasarte@unav.es ncasares@unav.es.
Juan J
http://orcid.org/0000-0003-1641-3881
JJ
Lasarte
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D023201:CD40 Ligand / Q000096:biosynthesis* / Q000235:genetics; D060908:CTLA-4 Antigen / Q000096:biosynthesis; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009369:Neoplasms / Q000628:therapy; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D000077157:Sorafenib; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C098680:Il17a protein, mouse; D020381:Interleukin-17; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D050778:NFATC Transcription Factors; D010446:Peptide Fragments; D010671:Phenylurea Compounds; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D023201:CD40 Ligand; D009536:Niacinamide; D007371:Interferon-gamma; D010047:Ovalbumin; D000077157:Sorafenib