The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus

Rachael Keating, Tomer Hertz, Marie Wehenkel, Tarsha L Harris, Benjamin A Edwards, Jennifer L McClaren, Scott A Brown, Sherri Surman, Zachary S Wilson, Philip Bradley, Julia Hurwitz, Hongbo Chi, Peter C Doherty, Paul G Thomas & Maureen A McGargill. Nat. Immunol., (2013) 14, 1266-1276.

Speaker: Wei-Han Deng (鄧暐翰)                             Time: 14:00~15:00, Nov. 12, 2014

Commentator: Dr. Ai-Li Shiau (蕭璦莉 老師)                Place: Room 601

Abstract

Vaccine development of Influenza A viruses have several limitations¹. One of the reason is influenza A viruses can easily rearrange gene segments between different strains, which present as variants of circulating ‘seasonal’ viruses. To predict which variants of hemagglutinin (HA) and neuraminidase (NA) might cause epidemic or pandemic potential in next season become a difficultlimitation. Using universal vaccines to target conserved epitopes will reduce the frequency of cross-reactive antibodies which have capacity for heterosubtypic protection². Affinity maturation steered the immune response into strain-specific responses to less cross-reactive responses. Serine-threonine kinase mTOR can promote class switching and affinity maturation in B cells.Rapamycin can inhibit mTOR activity and trigger cross-reactive responses which enhance heterosubtypic protection. To investigate the effect of rapamycin on vaccination, the authors infected miceintraperitoneally with HKx31 (an H3N2 subtype) during primary infection and infected mice intranasally withΔVn1203 (an H5N1 subtype) or A/Anhui/1/2013 (an H7N9 subtype) or PR8 (an H1N1 subtype) during secondary infection. During primary infection, the authors given C57BL/6 mice rapamycin or PBS by intraperitoneal injection. The result show that rapamycin enhancedheterosubtypic protection between different subtype influenza viruses. The authors next demonstrated that CD8⁺ T cells are dispensable for cross-protective immunity. On the contrary, CD4⁺ T cells and B cells are necessary for heterosubtypic protection. The authors also indicated the mechanism of the function of rapamycin. Rapamycin inhibits the proliferation of B cells and formation of GCs independently of class switching. Finally, the authors find that the antibody repertoire is different between rapamycin and PBS treatment. This cross-protective immunity have important implications for design of a vaccine against influenza virus.

References

1          Pica, N. & Palese, P. Toward a Universal Influenza Virus Vaccine: Prospects and Challenges. Annu Rev Med 64, 189-202, doi:DOI 10.1146/annurev-med-120611-145115 (2013).

2          Ekiert, D. C. et al. Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature 489, 526-+, doi:Doi 10.1038/Nature11414 (2012).