Essential role for autophagy in the maintenance of immunological memory against influenza infection

Abstract

Vaccination has been the most widely used strategy to protect against viral infections for centuries. However, the molecular mechanisms governing the long-term persistence of immunological memory in response to vaccines remain unclear. Here we show that autophagy has a critical role in the maintenance of memory B cells that protect against influenza virus infection. Memory B cells displayed elevated levels of basal autophagy with increased expression of genes that regulate autophagy initiation or autophagosome maturation. Mice with B cell–specific deletion of Atg7 (B/Atg7−/− mice) showed normal primary antibody responses after immunization against influenza but failed to generate protective secondary antibody responses when challenged with influenza viruses, resulting in high viral loads, widespread lung destruction and increased fatality. Our results suggest that autophagy is essential for the survival of virus-specific memory B cells in mice and the maintenance of protective antibody responses required to combat infections.

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Figure 1: Decreased spontaneous cell death and caspase signaling but constitutive autophagy in memory B cells.
Figure 2: Increased cell death in autophagy-deficient memory B cells.
Figure 3: Normal primary but defective secondary antibody responses in B/Atg7−/− mice.
Figure 4: Loss of memory B cells in the absence of Atg7.
Figure 5: Defective memory B cell responses to influenza infection in B/Atg7−/− mice.
Figure 6: B/Atg7−/− mice are defective in mounting protective immunity against influenza virus.

Change history

  • 28 April 2014

     In the version of this article initially published online, the legend for Figure 3c,d was incorrect. The mice used in Figure 3c,d were immunized as in Figure 3b, not as in Figure 3a. The error has been corrected for all versions of this article.

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Acknowledgements

We thank M. Komatsu of Tokyo Metropolitan Institute of Medical Science for providing Atg7flox/flox mice. We thank M. Schaefer and L.-Z. Song for technical assistance. This work was supported by grants from the US National Institutes of Health to J.W. (R01 GM087710), M.C. (R01DK083164), D.B.C. and F.K. (R01HL117181) and a US Department of Veterans Affairs merit award (to D.B.C. and F.K.).

Author information

M.C. designed and performed experiments, analyzed data and wrote the manuscript; M.J.H. performed viral infection, determined lung pathology and analyzed data; H.S. and L.W. performed experiments; X.S. assisted with experiments; B.E.G. provided the virus and advised on viral infections; D.B.C. and F.K. advised on influenza experiments and obtained human samples; and J.W. designed the study, analyzed data and wrote the manuscript.

Correspondence to Min Chen or Jin Wang.

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Chen, M., Hong, M., Sun, H. et al. Essential role for autophagy in the maintenance of immunological memory against influenza infection. Nat Med 20, 503–510 (2014) doi:10.1038/nm.3521

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