Vaccine study reveals link between immunity and cells' starvation response

Woodruff Health Sciences Center | Dec. 5, 2013


Lisa Newbern

Holly Korschun

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The yellow fever vaccine was one of the most effective in history and scientists have been teasing apart why, in hopes of duplicating its success.

In infected cells, the yellow fever vaccine induces autophagy, indicated here by the presence of green speckles. Red indicates vaccine antigens.



The results, published online Thursday by the journal Science,  shows that GCN2 is critical for the induction of immunity to the yellow fever vaccine, and suggest that vaccine additives (called adjuvants) that are effective in stimulating GCN2 and autophagy would be especially potent in stimulating long-lasting immunity.

"This reveals an unappreciated link between the ancient starvation response and vaccine-induced immunity, and highlights the power of system-wide approaches in revealing new insights," says senior author Bali Pulendran, PhD. "We were not thinking about the stress response pathway and immunity until our analysis pointed us in that direction."


The yellow fever vaccine was developed in the 1930s and has been administered to more than 500 million people. A single dose of the live attenuated viral yellow fever vaccine can protect against disease-causing forms of the virus for decades.

Investigators led by Pulendran have been dissecting immune responses to the yellow fever vaccine, taking a genome-wide "systems biology" approach. They started by looking at all the genes that are turned on a few days after human volunteers were vaccinated against yellow fever and asked: which genes’ activations are the signatures of especially strong immune responses later?

In particular, Pulendran and his colleagues looked for responses by CD8 killer T cells, which are important for eliminating virally-infected cells from the body. One gene that stuck out was GCN2, because it was induced quickly after vaccination and was a sign that the immune system would later respond with lots of CD8 T cells.


In the Science paper, Pulendran and his colleagues show that GCN2’s function is especially critical in dendritic cells, whose job is to "present" information about viruses and other pathogens to the rest of the immune system. Dendritic cells lacking GCN2 are less able to activate CD8 T cells, and mice that lacked GCN2 had impaired responses to yellow fever vaccine and to inhaled influenza vaccine, the researchers found.




Reference: R. Ravindran et al. Vaccine Activation of the Nutrient Sensor GCN2 in Dendritic Cells Enhances Antigen Presentation. Science DOI: 10.1126/science.1246829 (2013).