Journal
JOURNAL OF IMMUNOLOGY
Volume 192, Issue 11, Pages 5192-5200Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1302526
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Funding
- Swiss National Science Foundation Grant [125447]
- Promedica Foundation
- UBS Optimus Foundation
- Mexican National Council of Science and Technology (CONACyT) [SEP/CONACyT CB-2009-01-134501, SEP/CONACyT CB-2011-1-1-66946]
- Mexican Social Security Institute (IMSS)/Health Research Fund Project [FIS/IMSS/PROT/MD11/994, FIS/IMSS/PROT/C2007/049]
- CONACyT
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Abs play a significant role in protection against the intracellular bacterium Salmonella Typhi. In this article, we investigated how long-term protective IgM responses can be elicited by a S. Typhi outer-membrane protein C-and F-based subunit vaccine (porins). We found that repeated Ag exposure promoted a CD4(+) T cell-dependent germinal center reaction that generated mutated IgM-producing B cells and was accompanied by a strong expansion of IFN-gamma-secreting T follicular helper cells. Genetic ablation of individual cytokine receptors revealed that both IFN-gamma and IL-17 are required for optimal germinal center reactions and production of porin-specific memory IgM(+) B cells. However, more profound reduction of porin-specific IgM B cell responses in the absence of IFN-gamma R signaling indicated that this cytokine plays a dominant role. Importantly, mutated IgM mAbs against porins exhibited bactericidal capacity and efficiently augmented S. Typhi clearance. In conclusion, repeated vaccination with S. Typhi porins programs type I T follicular helper cell responses that contribute to the diversification of B cell memory and promote the generation of protective IgM Abs.
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