In vitro and in vivo down-regulation of regulatory T cell activity with a peptide inhibitor of TGF-beta1.
Down-regulation of CD4+CD25+ regulatory T (Treg) cell function might be beneficial to enhance the immunogenicity of viral and tumor vaccines or to induce breakdown of immunotolerance. Although the mechanism of suppression used by Treg cells remains controversial, it has been postulated that TGF-beta1 mediates their immunosuppressive activity. In this study, we show that P17, a short synthetic peptide that inhibits TGF-beta1 and TGF-beta2 developed in our laboratory, is able to inhibit Treg activity in vitro and in vivo. In vitro studies demonstrate that P17 inhibits murine and human Treg-induced unresponsiveness of effector T cells to anti-CD3 stimulation, in an MLR or to a specific Ag. Moreover, administration of P17 to mice immunized with peptide vaccines containing tumor or viral Ags enhanced anti-vaccine immune responses and improved protective immunogenicity against tumor growth or viral infection or replication. When CD4+ T cells purified from OT-II transgenic mice were transferred into C57BL/6 mice bearing s.c. EG.7-OVA tumors, administration of P17 improved their proliferation, reduced the number of CD4+Foxp3+ T cells, and inhibited tumor growth. Also, P17 prevented development of immunotolerance induced by oral administration of OVA by genetically modified Lactococcus lactis in DO11.10 transgenic mice sensitized by s.c. injection of OVA. These findings demonstrate that peptide inhibitors of TGF-beta may be a valuable tool to enhance vaccination efficacy and to break tolerance against pathogens or tumor Ags.
Center for Applied Medical Research, Division of Hepatology and Gene Therapy, University of Navarra, Pamplona, Spain.
Lucía
L
Gil-Guerrero
Javier
J
Dotor
Inge Louise
IL
Huibregtse
Noelia
N
Casares
Ana Belén
AB
López-Vázquez
Francesc
F
Rudilla
José Ignacio
JI
Riezu-Boj
Jacinto
J
López-Sagaseta
José
J
Hermida
Sander
S
Van Deventer
Jaione
J
Bezunartea
Diana
D
Llopiz
Pablo
P
Sarobe
Jesús
J
Prieto
Francisco
F
Borrás-Cuesta
Juan José
JJ
Lasarte
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D010455:Peptides / Q000494:pharmacology*; D020033:Protein Isoforms / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D053781:Transforming Growth Factor beta2 / Q000037:antagonists & inhibitors / Q000276:immunology
D019496:Cancer Vaccines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007166:Immunosuppressive Agents; D010455:Peptides; D020033:Protein Isoforms; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2