Combined NKT cell activation and influenza virus vaccination boosts memory CTL generation and protective immunity
- Carole Guillonneaua,
- Justine D. Minterna,
- François-Xavier Hubertb,
- Aeron C. Hurtc,
- Gurdyal S. Besrad,
- Steven Porcellie,
- Ian G. Barrc,
- Peter C. Dohertya,f,1,
- Dale I. Godfreya and
- Stephen J. Turnera,1
- aDepartment of Microbiology and Immunology, University of Melbourne, Melbourne 3010, Australia;
- bDivision of Immunology, Walter and Eliza Hall Institute of Medical Research, Melbourne 3010, Australia;
- cWHO Collaborating Centre for Reference and Research on Influenza, Parkville 3010, Australia;
- dSchool of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom;
- eDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Yeshiva University, New York, NY 10033; and
- fDepartment of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105
-
Contributed by Peter C. Doherty, December 29, 2008 (received for review December 7, 2008)
Abstract
Current influenza A virus vaccines do not generate significant immunity against serologically distinct influenza A virus subtypes and would thus be ineffective in the face of a pandemic caused by a novel variant emerging from, say, a wildlife reservoir. One possible solution would be to modify these vaccines so that they prime cross-reactive CD8+ cytotoxic T lymphocytes (CTL) cell-mediated immunity directed at conserved viral epitopes. A further strategy is to use novel adjuvants, such as the immunomodulatory glycolipid α-galactosylceramide (α-GalCer). We show here that giving α-GalCer with an inactivated influenza A virus has the paradoxical effect of diminishing acute CTL immunity via natural killer T (NKT) cell-dependent expression of indoleamine 2,3-dioxygenase (IDO), an important mediator of immune suppression, while at the same time promoting the survival of long-lived memory CTL populations capable of boosting protection against heterologous influenza A virus challenge. This enhancement of memory was likely due to the α-GalCer-induced upregulation of prosurvival genes, such as bcl-2, and points to the potential of α-GalCer as an adjuvant for promoting optimal, vaccine-induced CD8+ T cell memory.
Footnotes
- 1To whom correspondence may be addressed. E-mail: sjturn{at}unimelb.edu.au or pcd{at}unimelb.edu.au
-
Author contributions: C.G., D.I.G., and S.J.T. designed research; C.G., J.D.M., F.-X.H., and A.C.H. performed research; G.S.B., S.P., and I.G.B. contributed new reagents/analytic tools; C.G., J.D.M., F.-X.H., P.C.D., D.I.G., and S.J.T. analyzed data; and C.G., P.C.D., D.I.G., and S.J.T. wrote the paper.
-
The authors declare no conflict of interest.
-
This article contains supporting information online at www.pnas.org/cgi/content/full/0813309106/DCSupplemental.
