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

Chen M, Hong MJ, Sun H, Wang L, Shi X, Gilbert BE, Corry DB, Kheradmand F, Wang J - Nat. Med. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.

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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Defective memory B cell responses to influenza infection in B/Atg7−/− mice(a, b) HA-specific memory B cells in the spleen and lung of B/Atg7−/− mice or wild type controls two months after intranasal immunization with influenza virus at a sublethal dose of 7.5 TCID50. Unimmunized mice were used as negative controls (a). The total numbers of NP-specific memory B cells in the spleen and lung are presented (b). Data are representative of three independent experiments. Quantitative analyses are presented as mean ± SEM. **P<0.01 (6 mice/group). (c) Mice immunized as in (a) and re-challenged with influenza virus 2 months later. Anti-HA IgG or IgA in the sera or BAL fluids was quantitated 6 days after viral challenge. Antibody titers in the sera before the virus re-challenge are also shown. Data are representative of three independent experiments. Quantitative analyses are presented as mean ± SEM. **P<0.01 (n=10/group). (d) Anti-HA antibody secreting cells (ASC) in the spleen and lung of mice in (c) were quantitated by ELISPOT. Data are presented as mean ± SEM from three independent experiments. **P<0.01 (n=10/group).
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Figure 5: Defective memory B cell responses to influenza infection in B/Atg7−/− mice(a, b) HA-specific memory B cells in the spleen and lung of B/Atg7−/− mice or wild type controls two months after intranasal immunization with influenza virus at a sublethal dose of 7.5 TCID50. Unimmunized mice were used as negative controls (a). The total numbers of NP-specific memory B cells in the spleen and lung are presented (b). Data are representative of three independent experiments. Quantitative analyses are presented as mean ± SEM. **P<0.01 (6 mice/group). (c) Mice immunized as in (a) and re-challenged with influenza virus 2 months later. Anti-HA IgG or IgA in the sera or BAL fluids was quantitated 6 days after viral challenge. Antibody titers in the sera before the virus re-challenge are also shown. Data are representative of three independent experiments. Quantitative analyses are presented as mean ± SEM. **P<0.01 (n=10/group). (d) Anti-HA antibody secreting cells (ASC) in the spleen and lung of mice in (c) were quantitated by ELISPOT. Data are presented as mean ± SEM from three independent experiments. **P<0.01 (n=10/group).

Mentions: We determined whether the memory immune response against influenza A viruses was dependent on autophagy. Infection with influenza A induced influenza HA-specific IgG or IgA memory B cells in the spleen and lung of wild type mice (Fig. 5a, b and Supplementary Fig. 9). However, these memory B cells were significantly lower in B/Atg7−/− mice (Fig. 5a, b). The production of secondary anti-HA IgG or IgA antibodies were also severely impaired in B/Atg7−/− mice after re-challenging with the influenza virus (Fig. 5c). Moreover, B/Atg7−/− mice showed significantly decreased IgG or IgA ASC after re-challenging with influenza A (Fig. 5d). In contrast, T cell activation in response to primary or secondary influenza virus infection was not defective in B/Atg7−/− mice (Supplementary Fig. 10). Together, these data suggest that autophagy in B cells is essential for the maintenance of protective memory B cell responses against influenza infections.


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

Chen M, Hong MJ, Sun H, Wang L, Shi X, Gilbert BE, Corry DB, Kheradmand F, Wang J - Nat. Med. (2014)

Defective memory B cell responses to influenza infection in B/Atg7−/− mice(a, b) HA-specific memory B cells in the spleen and lung of B/Atg7−/− mice or wild type controls two months after intranasal immunization with influenza virus at a sublethal dose of 7.5 TCID50. Unimmunized mice were used as negative controls (a). The total numbers of NP-specific memory B cells in the spleen and lung are presented (b). Data are representative of three independent experiments. Quantitative analyses are presented as mean ± SEM. **P<0.01 (6 mice/group). (c) Mice immunized as in (a) and re-challenged with influenza virus 2 months later. Anti-HA IgG or IgA in the sera or BAL fluids was quantitated 6 days after viral challenge. Antibody titers in the sera before the virus re-challenge are also shown. Data are representative of three independent experiments. Quantitative analyses are presented as mean ± SEM. **P<0.01 (n=10/group). (d) Anti-HA antibody secreting cells (ASC) in the spleen and lung of mice in (c) were quantitated by ELISPOT. Data are presented as mean ± SEM from three independent experiments. **P<0.01 (n=10/group).
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Figure 5: Defective memory B cell responses to influenza infection in B/Atg7−/− mice(a, b) HA-specific memory B cells in the spleen and lung of B/Atg7−/− mice or wild type controls two months after intranasal immunization with influenza virus at a sublethal dose of 7.5 TCID50. Unimmunized mice were used as negative controls (a). The total numbers of NP-specific memory B cells in the spleen and lung are presented (b). Data are representative of three independent experiments. Quantitative analyses are presented as mean ± SEM. **P<0.01 (6 mice/group). (c) Mice immunized as in (a) and re-challenged with influenza virus 2 months later. Anti-HA IgG or IgA in the sera or BAL fluids was quantitated 6 days after viral challenge. Antibody titers in the sera before the virus re-challenge are also shown. Data are representative of three independent experiments. Quantitative analyses are presented as mean ± SEM. **P<0.01 (n=10/group). (d) Anti-HA antibody secreting cells (ASC) in the spleen and lung of mice in (c) were quantitated by ELISPOT. Data are presented as mean ± SEM from three independent experiments. **P<0.01 (n=10/group).
Mentions: We determined whether the memory immune response against influenza A viruses was dependent on autophagy. Infection with influenza A induced influenza HA-specific IgG or IgA memory B cells in the spleen and lung of wild type mice (Fig. 5a, b and Supplementary Fig. 9). However, these memory B cells were significantly lower in B/Atg7−/− mice (Fig. 5a, b). The production of secondary anti-HA IgG or IgA antibodies were also severely impaired in B/Atg7−/− mice after re-challenging with the influenza virus (Fig. 5c). Moreover, B/Atg7−/− mice showed significantly decreased IgG or IgA ASC after re-challenging with influenza A (Fig. 5d). In contrast, T cell activation in response to primary or secondary influenza virus infection was not defective in B/Atg7−/− mice (Supplementary Fig. 10). Together, these data suggest that autophagy in B cells is essential for the maintenance of protective memory B cell responses against influenza infections.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.

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.

Show MeSH
Related in: MedlinePlus