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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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CD8+, but not CD4+, T cell clones promote full recovery in  B cell–deficient mice. B cell–deficient (μKO) mice were infected intranasally with a 10 LD50 dose of mouse-adapted A/JAPAN/57 virus followed  by an intravenous injection of 107 cells. The cells transferred included  4D7 (⋄, a CD4+ clone), 11E4 (▴, a CD8+ clone), and B1.11 (•, a  CD8+ clone). Mice receiving intranasal influenza, but no cell transfer, are  denoted as □. C57Bl/6 mice receiving intranasal influenza without cell  transfer are also shown (✖). Each group represents 5–7 animals. Adoptive  transfer of these clones and media control into lethally challenged C57Bl/ 6 mice was done simultaneously as a control.
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Figure 4: CD8+, but not CD4+, T cell clones promote full recovery in B cell–deficient mice. B cell–deficient (μKO) mice were infected intranasally with a 10 LD50 dose of mouse-adapted A/JAPAN/57 virus followed by an intravenous injection of 107 cells. The cells transferred included 4D7 (⋄, a CD4+ clone), 11E4 (▴, a CD8+ clone), and B1.11 (•, a CD8+ clone). Mice receiving intranasal influenza, but no cell transfer, are denoted as □. C57Bl/6 mice receiving intranasal influenza without cell transfer are also shown (✖). Each group represents 5–7 animals. Adoptive transfer of these clones and media control into lethally challenged C57Bl/ 6 mice was done simultaneously as a control.

Mentions: In view of the evidence for both antibody independent clearance of virus during primary infection of μKO mice and enhanced resistance of these mice to lethal infection after priming, it was of interest to assess the contribution of virus-specific CD4+ and CD8+ effector T lymphocytes to recovery from infection in B cell–deficient mice. To examine this, we adoptively transferred clonal populations of A/JAPAN/57 virus-specific CD4+ and CD8+ T lymphocytes into lethally infected conventional and μKO mice. The clones used for these studies were H-2b haplotype-restricted CD4+ T cells (i.e., 4D7) and CD8+ T cells (i.e., 11E4 and B1.11), which have been previously characterized by us and have been shown to promote recovery when adoptively transferred into lethally infected C57Bl/6 mice (11). Fig. 4 shows the survival data for one adoptive transfer (representative of five independent experiments) carried out with these influenza-specific CD4+ and CD8+ T lymphocyte clonal effectors. As a control for each experiment, the same number of influenza-specific CD4+ or CD8+ T cell clones were adoptively transferred into lethally challenged C57Bl/6 mice, and all three clones consistently promoted 100% survival as previously published by this laboratory (11). The results of the adoptive transfers into C57Bl/6 mice are not shown as they are identical to those in our previous publication (11), but results of the viral challenge without concomitant clone transfer are shown in Fig. 4. In addition to promoting recovery in C57Bl/6 mice, both CD8+ T cell clones efficiently promoted recovery in lethally infected μKO mice (Fig. 4). On the other hand, the adoptively transferred clone of CD4+ T cells conferred partial protection in infected μKO mice with only 20% of the clone recipients surviving lethal infection (Fig. 4). In four other independent transfer experiments using these clonal populations of CD4+ and CD8+ T cells, the overall survival for lethally infected μKO recipients of the virus-specific CD4+ T cell clone ranged from 20 to 60%, whereas the CD8+ T cell clones reproducibly promoted recovery of 100% of infected μKO recipients.


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

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

CD8+, but not CD4+, T cell clones promote full recovery in  B cell–deficient mice. B cell–deficient (μKO) mice were infected intranasally with a 10 LD50 dose of mouse-adapted A/JAPAN/57 virus followed  by an intravenous injection of 107 cells. The cells transferred included  4D7 (⋄, a CD4+ clone), 11E4 (▴, a CD8+ clone), and B1.11 (•, a  CD8+ clone). Mice receiving intranasal influenza, but no cell transfer, are  denoted as □. C57Bl/6 mice receiving intranasal influenza without cell  transfer are also shown (✖). Each group represents 5–7 animals. Adoptive  transfer of these clones and media control into lethally challenged C57Bl/ 6 mice was done simultaneously as a control.
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Figure 4: CD8+, but not CD4+, T cell clones promote full recovery in B cell–deficient mice. B cell–deficient (μKO) mice were infected intranasally with a 10 LD50 dose of mouse-adapted A/JAPAN/57 virus followed by an intravenous injection of 107 cells. The cells transferred included 4D7 (⋄, a CD4+ clone), 11E4 (▴, a CD8+ clone), and B1.11 (•, a CD8+ clone). Mice receiving intranasal influenza, but no cell transfer, are denoted as □. C57Bl/6 mice receiving intranasal influenza without cell transfer are also shown (✖). Each group represents 5–7 animals. Adoptive transfer of these clones and media control into lethally challenged C57Bl/ 6 mice was done simultaneously as a control.
Mentions: In view of the evidence for both antibody independent clearance of virus during primary infection of μKO mice and enhanced resistance of these mice to lethal infection after priming, it was of interest to assess the contribution of virus-specific CD4+ and CD8+ effector T lymphocytes to recovery from infection in B cell–deficient mice. To examine this, we adoptively transferred clonal populations of A/JAPAN/57 virus-specific CD4+ and CD8+ T lymphocytes into lethally infected conventional and μKO mice. The clones used for these studies were H-2b haplotype-restricted CD4+ T cells (i.e., 4D7) and CD8+ T cells (i.e., 11E4 and B1.11), which have been previously characterized by us and have been shown to promote recovery when adoptively transferred into lethally infected C57Bl/6 mice (11). Fig. 4 shows the survival data for one adoptive transfer (representative of five independent experiments) carried out with these influenza-specific CD4+ and CD8+ T lymphocyte clonal effectors. As a control for each experiment, the same number of influenza-specific CD4+ or CD8+ T cell clones were adoptively transferred into lethally challenged C57Bl/6 mice, and all three clones consistently promoted 100% survival as previously published by this laboratory (11). The results of the adoptive transfers into C57Bl/6 mice are not shown as they are identical to those in our previous publication (11), but results of the viral challenge without concomitant clone transfer are shown in Fig. 4. In addition to promoting recovery in C57Bl/6 mice, both CD8+ T cell clones efficiently promoted recovery in lethally infected μKO mice (Fig. 4). On the other hand, the adoptively transferred clone of CD4+ T cells conferred partial protection in infected μKO mice with only 20% of the clone recipients surviving lethal infection (Fig. 4). In four other independent transfer experiments using these clonal populations of CD4+ and CD8+ T cells, the overall survival for lethally infected μKO recipients of the virus-specific CD4+ T cell clone ranged from 20 to 60%, whereas the CD8+ T cell clones reproducibly promoted recovery of 100% of infected μKO recipients.

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