Oxidative/reductive conjugation of mannan to antigen selects for T1 or T2 immune responses

The induction of CD8+ cytotoxic T lymphocytes (CTLs) is desirable for immunization against many diseases, and recombinant-synthetic peptide antigens are now favored agents to use. However, a major problem is how to induce CTLs, which requires a T1-type response to such synthetic antigens. We report...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1995-10, Vol.92 (22), p.10128-10132
Main Authors: Apostolopoulos, V, Pietersz, G A, Loveland, B E, Sandrin, M S, McKenzie, I F
Format: Article
Language:English
Subjects:
3T3 Cells
AIDS/HIV
Animals
Antibody Formation
Carbohydrates
CD8-Positive T-Lymphocytes - immunology
Cells, Cultured
Cytokines - biosynthesis
Cytotoxicity, Immunologic
Enzyme-Linked Immunosorbent Assay
Female
Humans
Immunity (Disease)
Immunoglobulin G - biosynthesis
Immunoglobulin G - classification
Interferon-gamma - biosynthesis
Interleukin-4 - biosynthesis
Leukocytes
Mannans - immunology
Medical research
Mice
Mice, Inbred BALB C
Mucin-1 - immunology
Oxidation-Reduction
Spleen - immunology
T-Lymphocyte Subsets - immunology
T-Lymphocytes, Cytotoxic - immunology
Tumor Cells, Cultured
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Summary:The induction of CD8+ cytotoxic T lymphocytes (CTLs) is desirable for immunization against many diseases, and recombinant-synthetic peptide antigens are now favored agents to use. However, a major problem is how to induce CTLs, which requires a T1-type response to such synthetic antigens. We report that T1-type (generating high CTL, low antibody) or T2-type (the reciprocal) responses can be induced by conjugation of the antigen to the carbohydrate polymer mannan: T1 responses are selected by using oxidizing conditions; T2 responses are selected by using reducing conditions for the conjugation. Using human MUC1 as a model antigen in mice, immunization with oxidized mannan-MUC1 fusion protein (ox-M-FP) led to complete tumor protection (challenge up to 5 x 10(7) MUC1+ tumor cells), CTLs, and a high CTL precursor (CTLp) frequency (1/6900), whereas immunization with reduced mannan-MUC1 FP (red-M-FP) led to poor protection after challenge with only 10(6) MUC1+ tumor cells, no CTLs, and a low CTLp frequency (1/87,800). Ox-M-FP selects for a T1 response (mediated here by CD8+ cells) with high interferon gamma (IFN-gamma) secretion, no interleukin 4 (IL-4), and a predominant IgG2a antibody response; red-M-FP selects for a T2-type response with IL-4 production and a high predominant IgG1 antibody response but no IFN-gamma.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.92.22.10128