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A more recent version of this article appeared on October 1, 2007

Published online before print August 3, 2007
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0206119

Received for publication February 27, 2006.
Revised March 5, 2007.
Accepted for publication May 14, 2007.

Article

Complement C5a anaphylatoxin is an innate determinant of dendritic cell-induced Th1 immunity to Mycobacterium bovis BCG infection in mice

Rachel A. Moulton *, Mary Anne Mashruwala *, Amanda K. Smith *, Devin R. Lindsey *, Rick A. Wetsel {dagger}, David L. Haviland {dagger}, Robert L. Hunter *, and Chinnaswamy Jagannath *@

*Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center, and {dagger}Institute of Molecular Medicine, University of Texas, Houston, Texas, USA

@ To whom correspondence should be addressed. E-mail: chinnaswamy.jagannath{at}uth.tmc.edu.


  Abstract

During acquired immunity to Mycobacterium bovis bacillus Calmette-Guerin (BCG) infection in mice, dendritic cells (DCs) present mycobacterial antigens to naïve 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 naïve 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 naïve 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 IFN-{gamma}+ CD4- and CD8-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.

Key Words: congenic C5 mice • IL-12 • IL-10 • IFN-{gamma} • tuberculosis






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