1. Complement C5a anaphylatoxin is an innate determinant of dendritic cell-induced Th1 immunity to Mycobacterium bovis BCG infection in mice.
- Author
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Moulton RA, Mashruwala MA, Smith AK, Lindsey DR, Wetsel RA, Haviland DL, Hunter RL, and Jagannath C
- Subjects
- Animals, CD40 Antigens biosynthesis, CD40 Antigens immunology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes pathology, Cells, Cultured, Coculture Techniques, Complement C5a biosynthesis, Complement C5a genetics, Dendritic Cells metabolism, Dendritic Cells pathology, Interferon-gamma immunology, Interferon-gamma metabolism, Interleukin-12 biosynthesis, Lung immunology, Lung metabolism, Lung microbiology, Lung pathology, Macrophages immunology, Macrophages metabolism, Macrophages microbiology, Macrophages pathology, Mice, Mice, Knockout, Th1 Cells metabolism, Th1 Cells pathology, Tuberculosis genetics, Tuberculosis metabolism, Tuberculosis pathology, Tuberculosis veterinary, Complement C5a immunology, Dendritic Cells immunology, Interleukin-12 immunology, Mycobacterium bovis immunology, Th1 Cells immunology, Tuberculosis immunology
- Abstract
During acquired immunity to Mycobacterium bovis bacillus Calmette-Guerin (BCG) infection in mice, dendritic cells (DCs) present mycobacterial antigens to naive T cells to prime an immune response. Complement C5a (anaphylatoxin) secreted by mycobacteria-infected macrophages regulates IL-12p70 production. As IL-12p70 regulates Th1 immunity against mycobacteria in mice, we examined the effects of C5a on IL-12p70 secretion by murine DCs and Th1 immunity. DCs cultured from C5-deficient (C5(-/-)) and -sufficient (C5(+/+)) mice were infected with BCG in the presence or absence of the C5a peptide. ELISA showed that C5(-/-) DCs secreted less IL-12p70 (600 pg/mL vs. 100 pg/mL) than C5(+/+) DCs, and they secreted more IL-10. Using immunophenotyping, reduced CD40 expression was found on C5(-/-) DCs after BCG infection. BCG-primed DCs were then cocultured with naive or BCG-immune T cells to differentiate them into IFN-gamma-secreting Th1 T cells. Coincident with increased IL-12p70 levels, BCG-primed C5(+/+) DCs cocultured with naive or immune C5(+/+) T cells showed a larger increase in CD4+ IFN-gamma/CD8+ IFN-gamma+ T cells compared with cocultured DCs and T cells from C5(-/-) mice. Thus, BCG-primed C5(+/+) DCs were better able to drive a Th1 response. Furthermore, BCG aerosol-infected C5(-/-) mice showed reduced CD4 and CD8 IFN-gamma-secreting T cells in the lungs, concurrent with an increased growth of BCG. Thus, C5a, an innate peptide, appears to play an important role in the generation of acquired immune responses in mice by regulating the Th1 response through modulation of IL-12p70 secretion from DCs.
- Published
- 2007
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