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Key role of T cell defects in age-related vulnerability to West Nile virus.

Brien JD, Uhrlaub JL, Hirsch A, Wiley CA, Nikolich-Zugich J - J. Exp. Med. (2009)

Bottom Line: Specific age-related defects in T cell responses against dominant WNV epitopes were detected at the level of cytokine and lytic granule production, each of which are essential for resistance against WNV, and in the ability to generate multifunctional anti-WNV effector T cells, which are believed to be critical for robust antiviral immunity.Consistent with a profound qualitative and quantitative defect in T cell immunity, old brains contained at least 12x fewer total effector CD8 T cells compared with adult mice at the peak of brain infection.These findings identify potential targets for immunomodulation and treatment to combat lethal WNV infection in the elderly.

View Article: PubMed Central - HTML - PubMed

Affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA.

ABSTRACT
West Nile virus (WNV) infection causes a life-threatening meningoencephalitis that becomes increasingly more prevalent over the age of 50 and is 40-50x more prevalent in people over the age of 70, compared with adults under the age of 40. In a mouse model of age-related vulnerability to WNV, we demonstrate that death correlates with increased viral titers in the brain and that this loss of virus control with age was the result of defects in the CD4 and CD8 T cell response against WNV. Specific age-related defects in T cell responses against dominant WNV epitopes were detected at the level of cytokine and lytic granule production, each of which are essential for resistance against WNV, and in the ability to generate multifunctional anti-WNV effector T cells, which are believed to be critical for robust antiviral immunity. In contrast, at the peak of the response, old and adult T cells exhibited superimposable peptide sensitivity. Most importantly, although the adult CD4 or CD8 T cells readily protected immunodeficient mice upon adoptive transfer, old T cells of either subset were unable to provide WNV-specific protection. Consistent with a profound qualitative and quantitative defect in T cell immunity, old brains contained at least 12x fewer total effector CD8 T cells compared with adult mice at the peak of brain infection. These findings identify potential targets for immunomodulation and treatment to combat lethal WNV infection in the elderly.

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Inability of aged CD4 and CD8 T cells to protect RAG-1−/− mice against lethal WNV infection. (A) Purified CD8 and CD4 T cells from C57BL/6 (closed squares), IFNγ−/− (open squares), or perforin−/− (closed triangles) mice were transferred into RAG-1−/− mice, which were then infected with 200 PFU WNV and scored for survival. WT T cells exhibited significantly enhanced protection when compared with RAG-1−/− mice with no transfer (closed circles, P < 0.0006) or RAG-1−/− mice receiving perforin−/− (P < 0.003) or IFN-γ−/− T cells (P < 0.01). (B) Young RAG-1−/− mice received no cells (closed diamonds) or received highly purified adult (squares) or old (inverted triangles) CD4 (closed symbols) or CD8 (open symbols) T cells (5 × 106 cells/mouse). Engraftment was verified after 24 h, with animals infected with 200 PFU WNV, and survival was scored thereafter. Adoptive transfer of old CD4 or CD8 T cells failed to confer any protection to RAG-1–deficient hosts, whereas transfer of adult CD4 (P < 0.0001) or CD8 (P < 0.01) T cells afforded a high degree of protection. Both parts of the figure were reproduced in three separate experiments.
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fig5: Inability of aged CD4 and CD8 T cells to protect RAG-1−/− mice against lethal WNV infection. (A) Purified CD8 and CD4 T cells from C57BL/6 (closed squares), IFNγ−/− (open squares), or perforin−/− (closed triangles) mice were transferred into RAG-1−/− mice, which were then infected with 200 PFU WNV and scored for survival. WT T cells exhibited significantly enhanced protection when compared with RAG-1−/− mice with no transfer (closed circles, P < 0.0006) or RAG-1−/− mice receiving perforin−/− (P < 0.003) or IFN-γ−/− T cells (P < 0.01). (B) Young RAG-1−/− mice received no cells (closed diamonds) or received highly purified adult (squares) or old (inverted triangles) CD4 (closed symbols) or CD8 (open symbols) T cells (5 × 106 cells/mouse). Engraftment was verified after 24 h, with animals infected with 200 PFU WNV, and survival was scored thereafter. Adoptive transfer of old CD4 or CD8 T cells failed to confer any protection to RAG-1–deficient hosts, whereas transfer of adult CD4 (P < 0.0001) or CD8 (P < 0.01) T cells afforded a high degree of protection. Both parts of the figure were reproduced in three separate experiments.

Mentions: We established a robust mouse model of the age-related susceptibility to WNV. In our hands, old mice exhibited increased susceptibility to WNV regardless of the infection route (i.p. or s.c.), the viral isolate of WNV Ia (NY-99, 31A, or 385–99; Table S1, Fig. 1; see Figs. 2 and 5; and not depicted), or the mouse strain (Fig. 1, C57BL/6; and see Figs. 2 and 5, C57BL/6; or Fig. S1, BALB/c) used, although, as expected, i.p infection produced lethal effects at a lower dose (1–20 PFU) compared with the more physiological s.c. infection (50–1,000 PFU). Overall, old mice were at least six times more susceptible to WNV as measured by survival rates over many viral concentrations (Fig. 1 A and not depicted). At low viral doses, that difference was drastically reduced and, in some experiments, disappeared (Fig. 1 A, Table S1, and not depicted), whereas at the high doses both old and adult animals succumbed to infection, suggesting that the viral dose is one of the principal determinants of selective mortality of old mice within a specific dose window.


Key role of T cell defects in age-related vulnerability to West Nile virus.

Brien JD, Uhrlaub JL, Hirsch A, Wiley CA, Nikolich-Zugich J - J. Exp. Med. (2009)

Inability of aged CD4 and CD8 T cells to protect RAG-1−/− mice against lethal WNV infection. (A) Purified CD8 and CD4 T cells from C57BL/6 (closed squares), IFNγ−/− (open squares), or perforin−/− (closed triangles) mice were transferred into RAG-1−/− mice, which were then infected with 200 PFU WNV and scored for survival. WT T cells exhibited significantly enhanced protection when compared with RAG-1−/− mice with no transfer (closed circles, P < 0.0006) or RAG-1−/− mice receiving perforin−/− (P < 0.003) or IFN-γ−/− T cells (P < 0.01). (B) Young RAG-1−/− mice received no cells (closed diamonds) or received highly purified adult (squares) or old (inverted triangles) CD4 (closed symbols) or CD8 (open symbols) T cells (5 × 106 cells/mouse). Engraftment was verified after 24 h, with animals infected with 200 PFU WNV, and survival was scored thereafter. Adoptive transfer of old CD4 or CD8 T cells failed to confer any protection to RAG-1–deficient hosts, whereas transfer of adult CD4 (P < 0.0001) or CD8 (P < 0.01) T cells afforded a high degree of protection. Both parts of the figure were reproduced in three separate experiments.
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fig5: Inability of aged CD4 and CD8 T cells to protect RAG-1−/− mice against lethal WNV infection. (A) Purified CD8 and CD4 T cells from C57BL/6 (closed squares), IFNγ−/− (open squares), or perforin−/− (closed triangles) mice were transferred into RAG-1−/− mice, which were then infected with 200 PFU WNV and scored for survival. WT T cells exhibited significantly enhanced protection when compared with RAG-1−/− mice with no transfer (closed circles, P < 0.0006) or RAG-1−/− mice receiving perforin−/− (P < 0.003) or IFN-γ−/− T cells (P < 0.01). (B) Young RAG-1−/− mice received no cells (closed diamonds) or received highly purified adult (squares) or old (inverted triangles) CD4 (closed symbols) or CD8 (open symbols) T cells (5 × 106 cells/mouse). Engraftment was verified after 24 h, with animals infected with 200 PFU WNV, and survival was scored thereafter. Adoptive transfer of old CD4 or CD8 T cells failed to confer any protection to RAG-1–deficient hosts, whereas transfer of adult CD4 (P < 0.0001) or CD8 (P < 0.01) T cells afforded a high degree of protection. Both parts of the figure were reproduced in three separate experiments.
Mentions: We established a robust mouse model of the age-related susceptibility to WNV. In our hands, old mice exhibited increased susceptibility to WNV regardless of the infection route (i.p. or s.c.), the viral isolate of WNV Ia (NY-99, 31A, or 385–99; Table S1, Fig. 1; see Figs. 2 and 5; and not depicted), or the mouse strain (Fig. 1, C57BL/6; and see Figs. 2 and 5, C57BL/6; or Fig. S1, BALB/c) used, although, as expected, i.p infection produced lethal effects at a lower dose (1–20 PFU) compared with the more physiological s.c. infection (50–1,000 PFU). Overall, old mice were at least six times more susceptible to WNV as measured by survival rates over many viral concentrations (Fig. 1 A and not depicted). At low viral doses, that difference was drastically reduced and, in some experiments, disappeared (Fig. 1 A, Table S1, and not depicted), whereas at the high doses both old and adult animals succumbed to infection, suggesting that the viral dose is one of the principal determinants of selective mortality of old mice within a specific dose window.

Bottom Line: Specific age-related defects in T cell responses against dominant WNV epitopes were detected at the level of cytokine and lytic granule production, each of which are essential for resistance against WNV, and in the ability to generate multifunctional anti-WNV effector T cells, which are believed to be critical for robust antiviral immunity.Consistent with a profound qualitative and quantitative defect in T cell immunity, old brains contained at least 12x fewer total effector CD8 T cells compared with adult mice at the peak of brain infection.These findings identify potential targets for immunomodulation and treatment to combat lethal WNV infection in the elderly.

View Article: PubMed Central - HTML - PubMed

Affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006, USA.

ABSTRACT
West Nile virus (WNV) infection causes a life-threatening meningoencephalitis that becomes increasingly more prevalent over the age of 50 and is 40-50x more prevalent in people over the age of 70, compared with adults under the age of 40. In a mouse model of age-related vulnerability to WNV, we demonstrate that death correlates with increased viral titers in the brain and that this loss of virus control with age was the result of defects in the CD4 and CD8 T cell response against WNV. Specific age-related defects in T cell responses against dominant WNV epitopes were detected at the level of cytokine and lytic granule production, each of which are essential for resistance against WNV, and in the ability to generate multifunctional anti-WNV effector T cells, which are believed to be critical for robust antiviral immunity. In contrast, at the peak of the response, old and adult T cells exhibited superimposable peptide sensitivity. Most importantly, although the adult CD4 or CD8 T cells readily protected immunodeficient mice upon adoptive transfer, old T cells of either subset were unable to provide WNV-specific protection. Consistent with a profound qualitative and quantitative defect in T cell immunity, old brains contained at least 12x fewer total effector CD8 T cells compared with adult mice at the peak of brain infection. These findings identify potential targets for immunomodulation and treatment to combat lethal WNV infection in the elderly.

Show MeSH
Related in: MedlinePlus