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Resistance to and recovery from lethal influenza virus infection in B lymphocyte-deficient mice.

Graham MB, Braciale TJ - J. Exp. Med. (1997)

Bottom Line: Cloned CD8+ effectors efficiently promoted recovery from lethal infection, whereas cloned CD4+ T cells conferred only partial protection.These results suggest that memory T lymphocytes can act independently of a humoral immune response in order to confer resistance to influenza infection in immune individuals.The potential implications of these results for vaccination against human influenza infection are discussed.

View Article: PubMed Central - PubMed

Affiliation: Beirne B. Carter Center for Immunology Research, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA. mbgraham@uic.edu

ABSTRACT
In the adaptive immune response to most viruses, both the cellular and humoral arms of the immune system play complementary roles in eliminating virus and virus-infected cells and in promoting recovery. To evaluate the relative contribution of CD4+ and CD8+ effector T lymphocytes in virus clearance and recovery, we have examined the host response to lethal type A influenza virus infection in B lymphocyte-deficient mice with a targeted disruption in the immunoglobulin mu heavy chain. Our results indicate that naive B cell-deficient mice have a 50- 100-fold greater susceptibility to lethal type A influenza virus infection than do wild type mice. However, after priming with sublethal doses of influenza, immune B cell-deficient animals show an enhanced resistance to lethal virus infection. This finding indicates that an antibody-independent immune-mediated antiviral mechanism accounts for the increased resistance to lethal virus challenge. To assess the contribution of influenza-specific CD4+ and CD8+ effector T cells in this process, defined clonal populations of influenza-specific CD4+ and CD8+ effector T cells were adoptively transferred into lethally infected B cell-deficient mice. Cloned CD8+ effectors efficiently promoted recovery from lethal infection, whereas cloned CD4+ T cells conferred only partial protection. These results suggest that memory T lymphocytes can act independently of a humoral immune response in order to confer resistance to influenza infection in immune individuals. The potential implications of these results for vaccination against human influenza infection are discussed.

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μKO mice can initiate and maintain an influenza-specific  CTL response after challenge with influenza virus. (a) Lungs were removed from μKO (shaded bars) and C57BL/6 (open bars) mice on day 12  after intranasal viral challenge with a sublethal dose of A/JAPAN/57 (attenuated strain). Cell suspensions from the lungs were obtained by processing through a sieve, and were Ficoll purified and plated for a final effector/targer (E/T) ratio of 50:1. Assay time was 6 h and spontaneous  release for all targets was <20%. Results of two separate experiments with  two mice per experimental group are shown. (b) Influenza specific bulks  from four individual μKO (shaded bars) and from C57BL/6 (open bars)  mice were tested for their ability to lyse uninfected and A/JAPAN/57 infected class II negative (EL4) and class I and II positive (LB15.13) target  cells in a standard chromium release assay. Assay time = 6 h; E/T = 10:1.  Spontaneous release for all targets was <15%. Experiment is representative of three separate experiments.
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Figure 2: μKO mice can initiate and maintain an influenza-specific CTL response after challenge with influenza virus. (a) Lungs were removed from μKO (shaded bars) and C57BL/6 (open bars) mice on day 12 after intranasal viral challenge with a sublethal dose of A/JAPAN/57 (attenuated strain). Cell suspensions from the lungs were obtained by processing through a sieve, and were Ficoll purified and plated for a final effector/targer (E/T) ratio of 50:1. Assay time was 6 h and spontaneous release for all targets was <20%. Results of two separate experiments with two mice per experimental group are shown. (b) Influenza specific bulks from four individual μKO (shaded bars) and from C57BL/6 (open bars) mice were tested for their ability to lyse uninfected and A/JAPAN/57 infected class II negative (EL4) and class I and II positive (LB15.13) target cells in a standard chromium release assay. Assay time = 6 h; E/T = 10:1. Spontaneous release for all targets was <15%. Experiment is representative of three separate experiments.

Mentions: To determine if recovery from primary intranasal influenza infection in μKO mice correlated with the presence of cellular immune effectors, e.g., CTLs, at the site of infection, groups of μKO and age-matched C57Bl/6 mice were sublethally infected with the mouse-adapted A/JAPAN/57 virus. On day 12 after infection, the mice were killed, lungs were excised, and mononuclear cells infiltrating the lungs were collected and tested for in vitro cytolytic activity. As Fig. 2 a shows, mononuclear cells from the lungs of infected μKO mice and from conventional mice exhibited a comparable degree of specific cytolytic activity on virus-infected target cells in vitro. Similar results were obtained when T cells were obtained at d 12 from lungs of wild-type and B cell–deficient mice recovering from nonlethal intranasal infection with an attenuated A/JAPAN/57 virus preparation (data not shown).


Resistance to and recovery from lethal influenza virus infection in B lymphocyte-deficient mice.

Graham MB, Braciale TJ - J. Exp. Med. (1997)

μKO mice can initiate and maintain an influenza-specific  CTL response after challenge with influenza virus. (a) Lungs were removed from μKO (shaded bars) and C57BL/6 (open bars) mice on day 12  after intranasal viral challenge with a sublethal dose of A/JAPAN/57 (attenuated strain). Cell suspensions from the lungs were obtained by processing through a sieve, and were Ficoll purified and plated for a final effector/targer (E/T) ratio of 50:1. Assay time was 6 h and spontaneous  release for all targets was <20%. Results of two separate experiments with  two mice per experimental group are shown. (b) Influenza specific bulks  from four individual μKO (shaded bars) and from C57BL/6 (open bars)  mice were tested for their ability to lyse uninfected and A/JAPAN/57 infected class II negative (EL4) and class I and II positive (LB15.13) target  cells in a standard chromium release assay. Assay time = 6 h; E/T = 10:1.  Spontaneous release for all targets was <15%. Experiment is representative of three separate experiments.
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Related In: Results  -  Collection

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Figure 2: μKO mice can initiate and maintain an influenza-specific CTL response after challenge with influenza virus. (a) Lungs were removed from μKO (shaded bars) and C57BL/6 (open bars) mice on day 12 after intranasal viral challenge with a sublethal dose of A/JAPAN/57 (attenuated strain). Cell suspensions from the lungs were obtained by processing through a sieve, and were Ficoll purified and plated for a final effector/targer (E/T) ratio of 50:1. Assay time was 6 h and spontaneous release for all targets was <20%. Results of two separate experiments with two mice per experimental group are shown. (b) Influenza specific bulks from four individual μKO (shaded bars) and from C57BL/6 (open bars) mice were tested for their ability to lyse uninfected and A/JAPAN/57 infected class II negative (EL4) and class I and II positive (LB15.13) target cells in a standard chromium release assay. Assay time = 6 h; E/T = 10:1. Spontaneous release for all targets was <15%. Experiment is representative of three separate experiments.
Mentions: To determine if recovery from primary intranasal influenza infection in μKO mice correlated with the presence of cellular immune effectors, e.g., CTLs, at the site of infection, groups of μKO and age-matched C57Bl/6 mice were sublethally infected with the mouse-adapted A/JAPAN/57 virus. On day 12 after infection, the mice were killed, lungs were excised, and mononuclear cells infiltrating the lungs were collected and tested for in vitro cytolytic activity. As Fig. 2 a shows, mononuclear cells from the lungs of infected μKO mice and from conventional mice exhibited a comparable degree of specific cytolytic activity on virus-infected target cells in vitro. Similar results were obtained when T cells were obtained at d 12 from lungs of wild-type and B cell–deficient mice recovering from nonlethal intranasal infection with an attenuated A/JAPAN/57 virus preparation (data not shown).

Bottom Line: Cloned CD8+ effectors efficiently promoted recovery from lethal infection, whereas cloned CD4+ T cells conferred only partial protection.These results suggest that memory T lymphocytes can act independently of a humoral immune response in order to confer resistance to influenza infection in immune individuals.The potential implications of these results for vaccination against human influenza infection are discussed.

View Article: PubMed Central - PubMed

Affiliation: Beirne B. Carter Center for Immunology Research, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA. mbgraham@uic.edu

ABSTRACT
In the adaptive immune response to most viruses, both the cellular and humoral arms of the immune system play complementary roles in eliminating virus and virus-infected cells and in promoting recovery. To evaluate the relative contribution of CD4+ and CD8+ effector T lymphocytes in virus clearance and recovery, we have examined the host response to lethal type A influenza virus infection in B lymphocyte-deficient mice with a targeted disruption in the immunoglobulin mu heavy chain. Our results indicate that naive B cell-deficient mice have a 50- 100-fold greater susceptibility to lethal type A influenza virus infection than do wild type mice. However, after priming with sublethal doses of influenza, immune B cell-deficient animals show an enhanced resistance to lethal virus infection. This finding indicates that an antibody-independent immune-mediated antiviral mechanism accounts for the increased resistance to lethal virus challenge. To assess the contribution of influenza-specific CD4+ and CD8+ effector T cells in this process, defined clonal populations of influenza-specific CD4+ and CD8+ effector T cells were adoptively transferred into lethally infected B cell-deficient mice. Cloned CD8+ effectors efficiently promoted recovery from lethal infection, whereas cloned CD4+ T cells conferred only partial protection. These results suggest that memory T lymphocytes can act independently of a humoral immune response in order to confer resistance to influenza infection in immune individuals. The potential implications of these results for vaccination against human influenza infection are discussed.

Show MeSH
Related in: MedlinePlus