Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 1998 Jul 20;188(2):223-32.
doi: 10.1084/jem.188.2.223.

Contribution of virus-specific CD8+ cytotoxic T cells to virus clearance or pathologic manifestations of influenza virus infection in a T cell receptor transgenic mouse model

D Moskophidis  1 , D Kioussis
Affiliations

Contribution of virus-specific CD8+ cytotoxic T cells to virus clearance or pathologic manifestations of influenza virus infection in a T cell receptor transgenic mouse model

D Moskophidis et al. J Exp Med. .

Abstract

The ability of influenza virus to evade immune surveillance by neutralizing antibodies (Abs) directed against its variable surface antigens provides a challenge to the development of effective vaccines. CD8+ cytotoxic T lymphocytes (CTLs) restricted by class I major histocompatibility complex molecules are important in establishing immunity to influenza virus because they recognize internal viral proteins which are conserved between multiple viral strains. In contrast, protective Abs are strain-specific. However, the precise role of effector CD8+ CTLs in protection from influenza virus infection, critical for understanding disease pathogenesis, has not been well defined. In transgenic mice with a very high frequency of antiinfluenza CTL precursors, but without protective Abs, CD8+ CTLs conferred protection against low dose viral challenge, but exacerbated viral pathology and caused mortality at high viral dose. The data suggest a dual role for CD8+ CTLs against influenza, which may present a challenge to the development of effective CTL vaccines. Effector mechanisms used by CD8+ CTLs in orchestrating clearance of virus and recovery from experimental influenza infection, or potentiation of lethal pathology, are discussed.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Protection of mice against influenza A virus infection was observed by reduction of viral titers in lungs and survival rate, correlating with levels of antiviral Abs. F5-Tg or C57BL/10 control mice were infected with A/NT/60/68 (A and B, E and F, and I and J) or X31 (C and D, G and H, and K and L) influenza A viruses. (A–D) Mice were infected with 107 PFU (filled circles) or ≤106 PFU (filled triangles) of influenza A virus, and percent survival is shown for groups of 10–15 mice. (E–H) Titer of antiviral IgG (open circles) or IgM (filled circles) in serum of mice infected with 106 PFU of influenza A virus was determined. Values shown for Ab activity are mean log (ELISA titer) ± SEM of three mice. (I–L) Virus in lungs was measured in separate groups of mice infected with 106 PFU of influenza A virus. The virus titer is shown as mean log10 TCID50 per gram of lung ± SEM of three to five mice.
Figure 2
Figure 2
In the absence of protective antiviral Abs, CTLs in the lung tissue conferred protection against low viral challenge, but exacerbated disease at high viral doses. F5–RAG-1−/− (filled circles) or RAG-1−/− (open circles) mice were infected with A/NT/60/68 (left) or X31 (right) influenza A viruses. Percent survival is shown for groups of 10–15 mice. The virus was administrated intranasally at a dose of (A) 107, (B) 106, (C) 105, (D) 104, or (E) 102 PFU. Percent survival was significantly greater in F5–RAG-1−/− mice infected with 107 (P <0.0001 by Wilcoxon test) or 105 PFU (P <0.0001) of A/NT/60/68 than in control infected RAG-1−/− mice (A and B, left). No significant differences (P >0.09) were observed between the same strains of mice infected with X31 (A and B, right).
Figure 3
Figure 3
CTLs are protective against lethal influenza if they are able to control viral replication in lung tissue at the onset of viral infection. Virus titers in lung tissue of F5–RAG-1−/− (filled circles) or RAG-1−/− (open circles) mice infected with A/NT/60/68 (left) or X31 (right) influenza A viruses are expressed as mean log10 TCID50 per gram of lung of three to five mice. Mice are infected intranasally at doses of (A) 107, (B) 105, (C) 103, or (D) 10 PFU.
Figure 4
Figure 4
Kinetics of total inflammatory cells versus transgenic CTLs in BAL of mice infected with influenza A virus. F5–RAG-1−/− mice were infected intranasally with (A) 107, (B) 104, or (C) 102 PFU of A/ NT/60/68, or with (D) 107 PFU of control X31 virus (squares). In addition, (D) RAG-1−/− mice infected with 107 PFU of A/ NT/60/68 were included as controls (triangles). The numbers of inflammatory cells in BAL (open symbols) are indicated as mean ± SEM log10 per lung of three to five mice. BAL samples (total volume 1 ml per lung) containing <104 cells per ml (the limit of detection of our hemocytometer counting assay) were estimated as 104 cells per lung. Tg-CTLs (filled symbols) were detected in the same samples by staining cells with Abs specific for Vβ11, CD8 and analysis by flow cytometry. Absolute numbers of Tg-CTLs were calculated as percent transgenic positive cells by flow cytometry multiplied by total cell number. Populations <1% were considered undetectable.
Figure 5
Figure 5
Histological examination of lung tissue. Lungs were taken on day 6 or 8 from F5–RAG-1−/− transgenic mice infected with (A) 102 PFU of A/NT/60/68, (B) 107 PFU of A/NT/60/68, or (C) 107 PFU of X31 influenza A virus. (D) Lung tissue of a control uninfected F5–RAG-1−/− mouse.
Figure 6
Figure 6
The effect of administration of anti–IFN-γ on mortality, elimination of pulmonary virus, and numbers of Tg-CTLs versus total cell counts in the BAL of influenza virus–infected F5–RAG-1−/− mice. F5– RAG-1−/− mice were infected intranasally with a lethal dose of 107 PFU (left) or a sublethal dose of 102 PFU (right) of A/NT/60/68. Mice were treated with anti–IFN-γ mAb (filled circles) as described in Materials and Methods, or with PBS as control (open circles). (A and B) Percent survival is shown for groups of 5–10 mice. (C and D) Virus titers in lung tissue were expressed as mean log10 TCID50 per gram of lung of three to five mice. (E and F) Tg-CTLs were detected in the same samples by staining cells with Abs specific for Vβ11, CD8 and analysis by flow cytometry, and were expressed as mean ± SEM log10 per lung of three mice. (G and H) The numbers of inflammatory cells in BAL were indicated as mean ± SEM log10 per lung of three mice.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Palese P, Young JF. Variation of influenza A, B, and C viruses. Science. 1982;215:1468–1474. - PubMed
    1. Webster, R.G., W.G. Laver, and G.M. Air. 1983. Antigenic variation among type A influenza viruses. In Genetics of Influenza Viruses. P. Palese and D.W. Kingsbury, editors. Springer-Verlag, Vienna/New York. 127–168.
    1. Gorman OT, Bean WJ, Webster RG. Evolutionary processes in influenza viruses: divergence, rapid evolution, and stasis. Curr Top Microbiol Immunol. 1992;176:75–97. - PubMed
    1. Yewdell JW, Webster RG, Gerhard W. Antigen variation in three distinct determinants of an influenza A haemagglutinin molecule. Nature. 1979;279:246–248. - PubMed
    1. Townsend ARM, Bodmer H. Antigen recognition by class I-restricted T lymphocytes. Annu Rev Immunol. 1989;7:601–624. - PubMed

Publication types

MeSH terms

Substances