Targeting of antigens to B cells augments antigen-specific T-cell responses and breaks immune tolerance to tumor-associated antigen MUC1

• Published in: Blood 2008-10, Vol.112 (7), p.2817-2825
• Main Authors: Ding, Chuanlin, Wang, Li, Marroquin, Jose, Yan, Jun
• Format: Article
• Language: English
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Animals; Antibodies - pharmacology; Antigens, CD19 - immunology; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; Biological and medical sciences; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell interactions; Cell Line; Cell Proliferation - drug effects; Cell Survival - drug effects; Clonal Anergy - drug effects; Drug Screening Assays, Antitumor; Epitopes - immunology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immune Tolerance - drug effects; Immune Tolerance - immunology; Immunobiology; Immunoglobulin Isotypes; Lymphocyte Activation - drug effects; Lymphocyte Depletion; Mice; Mice, Inbred C57BL; Mucin-1 - immunology; Neoplasms - immunology; Neoplasms - therapy; Oligodeoxyribonucleotides - pharmacology; Ovalbumin - immunology; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Vaccination
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-05-157396

B cells are antibody (Ab)–secreting cells as well as potent antigen (Ag)–presenting cells that prime T-cell activation, which evokes great interest in their use for vaccine development. Here, we targeted ovalbumin (OVA) to B cells via CD19 and found that a single low dose of anti–CD19-OVA conjugates, but not isotype mAb-OVA, stimulated augmented CD4 and CD8 T-cell proliferation and expansion. Administration of TLR9 agonist CpG could significantly enhance long-term T-cell survival. Similar results were obtained when the tumor-associated Ag MUC1 was delivered to B cells. MUC1 transgenic (Tg) mice were previously found to lack effective T-cell help and produce low-titer of anti-MUC1 Abs after vaccination. Targeting MUC1 to B cells elicited high titer of anti-MUC1 Abs with different isotypes, predominantly IgG2a and IgG2b, in MUC1 Tg mice. The isotype switching of anti-MUC1 Ab was CD4 dependent. In addition, IFN-γ–producing CD8 T cells and in vivo cytolytic activity were significantly increased in these mice. The mice also showed significant resistance to MUC1+ lymphoma cell challenge both in the prophylactic and therapeutic settings. We conclude that Ags targeting to B cells stimulate CD4 and CD8 T-cell responses as well as Th-dependent humoral immune responses.