Abstract
α-galactosylceramide (α-GalCer) is the prototypical lipid ligand for invariant NKT cells. Recent studies have proposed that α-GalCer is an effective adjuvant in vaccination against a range of immune challenges, however its mechanism of action has not been completely elucidated. A variety of delivery methods have been examined including pulsing dendritic cells with α-GalCer to optimize the potential of α-GalCer. These methods are currently being used in a variety of clinical trials in patients with advanced cancer but cannot be used in the context of vaccine development against pathogens due to their complexity. Using a simple delivery method, we evaluated α-GalCer adjuvant properties, using the mouse model for cytomegalovirus (MCMV). We measured several key parameters of the immune response to MCMV, including inflammation, effector, and central memory CD8+ T cell responses. We found that α-GalCer injection at the time of the infection decreases viral titers, alters the kinetics of the inflammatory response, and promotes both increased frequencies and numbers of virus-specific memory CD8+ T cells. Overall, our data suggest that iNKT cell activation by α-GalCer promotes the development of long-term protective immunity through increased fitness of central memory CD8+ T cells, as a consequence of reduced inflammation.
Highlights
Adjuvants are mediators that enhance the natural immune response
We present a model in which adequate iNKT cell activation could potentially promote long-term immunity and help prevent viral reactivation
Results a-GalCer treatment interferes with model for cytomegalovirus (MCMV) induced cytokine production a-GalCer treatment results in rapid production of IFN-c and IL-4, as well as other cytokines in the serum at 4 hours posttreatment as a consequence of direct iNKT cell activation (Fig. 1 and data not shown)
Summary
Adjuvants are mediators that enhance the natural immune response. Two vaccine adjuvants are approved in the United States for prophylactic vaccination; aluminum adjuvants (Alum) and monophosphoryl lipid A (MPLA). Alum is currently used to boost immune responses in conjunction with a number of vaccines including those against hepatitis A, tetanus, and influenza, while MPLA (a derivative of Salmonella minnesota LPS) is currently used as an adjuvant for the human papillomavirus vaccine [1]. Cellmediated immunity marked by robust CD8+ T cell responses is critical for developing efficacious vaccines against diseases such as malaria and human immunodeficiency virus. Previous attempts to generate vaccines against a variety of diseases including HIV, malaria and tuberculosis have been mostly unsuccessful. To prevent these infections, it is believed that vaccines will need to induce the generation of an adequate and strong CD8+ T cell memory response [3]. Using a variety of cell surface markers, several groups have been able to distinguish memory precursor effector cells (MPECs) as CD8+ T cells that have a potential to survive and become long-lived memory CD8+ T cells from short-lived effector cells (SLECs) [6,7]
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