CD4+/CD25+ regulatory cells inhibit activation of tumor-primed CD4+ T cells with IFN-gamma-dependent antiangiogenic activity, as well as long-lasting tumor immunity elicited by peptide vaccination

• Published in: The Journal of immunology (1950) Vol. 171; no. 11; pp. 5931 - 5939
• Main Authors: Casares, Noelia, Arribillaga, Laura, Sarobe, Pablo, Dotor, Javier, Lopez-Diaz de Cerio, Ascensión, Melero, Ignacio, Prieto, Jesús, Borrás-Cuesta, Francisco, Lasarte, Juan J
• Format: Journal Article
• Language: English
• Published: United States 01-12-2003
• Subjects: Adoptive Transfer; Angiogenesis Inhibitors - biosynthesis; Angiogenesis Inhibitors - metabolism; Angiogenesis Inhibitors - physiology; Animals; Antigens, Neoplasm - administration & dosage; Antigens, Neoplasm - immunology; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - transplantation; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Colonic Neoplasms - blood supply; Colonic Neoplasms - immunology; Colonic Neoplasms - prevention & control; Down-Regulation - immunology; Epitopes, T-Lymphocyte - administration & dosage; Epitopes, T-Lymphocyte - immunology; Female; Immunologic Memory - immunology; Interferon-gamma - biosynthesis; Interferon-gamma - metabolism; Interferon-gamma - physiology; Lymphocyte Activation - immunology; Lymphocyte Depletion; Mice; Mice, Inbred BALB C; Mice, Knockout; Neoplasm Transplantation - immunology; Peptides - administration & dosage; Peptides - immunology; Receptors, Interleukin-2 - biosynthesis; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - transplantation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.171.11.5931

CD25(+) regulatory T (T reg) cells suppress the activation/proliferation of other CD4(+) or CD8(+) T cells in vitro. Also, down-regulation of CD25(+) T reg cells enhance antitumor immune responses. In this study, we show that depletion of CD25(+) T reg cells allows the host to induce both CD4(+) and CD8(+) antitumoral responses following tumor challenge. Simultaneous depletion of CD25(+) and CD8(+) cells, as well as adoptive transfer experiments, revealed that tumor-specific CD4(+) T cells, which emerged in the absence of CD25(+) T reg cells, were able to reject CT26 colon cancer cells, a MHC class II-negative tumor. The antitumoral effect mediated by CD4(+) T cells was dependent on IFN-gamma production, which exerted a potent antiangiogenic activity. The capacity of the host to mount this antitumor response is lost once the number of CD25(+) T reg cells is restored over time. However, CD25(+) T reg cell depletion before immunization with AH1 (a cytotoxic T cell determinant from CT26 tumor cells) permits the induction of a long-lasting antitumoral immune response, not observed if immunization is conducted in the presence of regulatory cells. A study of the effect of different levels of depletion of CD25(+) T reg cells before immunization with the peptide AH1 alone, or in combination with a Th determinant, unraveled that Th cells play an important role in overcoming the suppressive effect of CD25(+) T reg on the induction of long-lasting cellular immune responses.