Abstract
Th1 immunity protects against tuberculosis infection in mice and humans. The widely used BCG vaccine primes CD4 and CD8 T cells through signaling mechanisms from dendritic cells and macrophages. The latter express MHC-II and MHC-I molecules through which peptides from BCG vaccine are presented to CD4 and CD8 T cells, respectively. Since BCG sequesters within a phagosome that does not fuse with lysosomes, generation of peptides within antigen-presenting cells infected with BCG occurs with reduced efficiency. We demonstrate that activation of DCs containing BCG vaccine with rapamycin leads to an enhanced ability of DC vaccines to immunize mice against tuberculosis. Coadministration of rapamycin with BCG vaccine also enhanced Th1 immunity. We propose that rapamycin-mediated increase in Th1 responses offers novel models to study mTOR-mediated regulation of immunity.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Luo, H., W. Duguid, H. Chen, M. Maheu, and J. Wu. 1994. The effect of rapamycin on T cell development in mice. Eur J Immunol 24:692–701.
Anderson, K. M., and J. C. Zimring. 2006. Rapamycin prolongs susceptibility of responding T cells to tolerance induction by CD8+ veto cells. Transplantation 81:88–94.
Araki, K., A. P. Turner, V. O. Shaffer, S. Gangappa, S. A. Keller, M. F. Bachmann, C. P. Larsen, and R. Ahmed. 2009. mTOR regulates memory CD8 T-cell differentiation. Nature 460:108–112.
Ferrer, I. R., M. E. Wagener, J. M. Robertson, A. P. Turner, K. Araki, R. Ahmed, A. D. Kirk, C. P. Larsen, and M. L. Ford. Cutting edge: Rapamycin augments pathogen-specific but not graft-reactive CD8+ T cell responses. J Immunol 185:2004–2008.
Saemann, M. D., M. Haidinger, M. Hecking, W. H. Horl, and T. Weichhart. 2009. The multifunctional role of mTOR in innate immunity: implications for transplant immunity. Am J Transplant 9:2655–2661.
Jagannath, C., D. R. Lindsey, S. Dhandayuthapani, Y. Xu, R. L. Hunter, Jr., and N. T. Eissa. 2009. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med 15:267–276.
Clemens, D. L., and M. A. Horwitz. 1996. The Mycobacterium tuberculosis phagosome interacts with early endosomes and is accessible to exogenously administered transferrin. J Exp Med 184:1349–1355.
Deretic, V., and R. A. Fratti. 1999. Mycobacterium tuberculosis phagosome. Mol Microbiol 31:1603–1609.
Russell, D. G. 2001. Mycobacterium tuberculosis: here today, and here tomorrow. Nat Rev Mol Cell Biol 2:569–577.
Singh, C. R., R. A. Moulton, L. Y. Armitige, A. Bidani, M. Snuggs, S. Dhandayuthapani, R. L. Hunter, and C. Jagannath. 2006. Processing and presentation of a mycobacterial antigen 85B epitope by murine macrophages is dependent on the phagosomal acquisition of vacuolar proton ATPase and in situ activation of cathepsin D. J Immunol 177:3250–3259.
Soualhine, H., A. E. Deghmane, J. Sun, K. Mak, A. Talal, Y. Av-Gay, and Z. Hmama. 2007. Mycobacterium bovis bacillus Calmette-Guerin secreting active cathepsin S stimulates expression of mature MHC class II molecules and antigen presentation in human macrophages. J Immunol 179:5137–5145.
Rao, R. R., Q. Li, K. Odunsi, and P. A. Shrikant. The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 32:67–78.
Sathaliyawala, T., W. E. O’Gorman, M. Greter, M. Bogunovic, V. Konjufca, Z. E. Hou, G. P. Nolan, M. J. Miller, M. Merad, and B. Reizis. Mammalian target of rapamycin controls dendritic cell development downstream of Flt3 ligand signaling. Immunity 33:597–606.
Acknowledgments
This study was supported by AI49534 and AI78420. The authors acknowledge the technical assistance of Arshad Khan, Kari Herdtner, and Devin R. Lindsey.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Jagannath, C., Bakhru, P. (2012). Rapamycin-Induced Enhancement of Vaccine Efficacy in Mice. In: Weichhart, T. (eds) mTOR. Methods in Molecular Biology, vol 821. Humana Press. https://doi.org/10.1007/978-1-61779-430-8_18
Download citation
DOI: https://doi.org/10.1007/978-1-61779-430-8_18
Published:
Publisher Name: Humana Press
Print ISBN: 978-1-61779-429-2
Online ISBN: 978-1-61779-430-8
eBook Packages: Springer Protocols