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Antiviral CD8+ T cell responses in neonatal mice: susceptibility to polyoma virus-induced tumors is associated with lack of cytotoxic function by viral antigen-specific T cells.

Moser JM, Altman JD, Lukacher AE - J. Exp. Med. (2001)

Bottom Line: Using D(k) tetramers containing the dominant antipolyoma CD8(+) T cell epitope, middle T protein (MT)389-397, and intracellular interferon gamma staining, we enumerated MT389-specific CD8(+) T cells in infected neonates having opposite susceptibilities to polyoma virus-induced tumors.Upon in vitro restimulation with infected antigen-presenting cells, CD8(+) T cells from acutely infected susceptible neonates acquired strong MT389-specific cytotoxicity.These findings indicate that polyoma-specific CD8(+) T cells are armed with, but restrained from deploying, their cytotoxic effector function in mice susceptible to polyoma virus tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Emory University School of Medicine, Wooodruff Memorial Research Building, 1639 Pierce Dr., Atlanta, Georgia 30322, USA.

ABSTRACT
Polyoma virus is a potent oncogenic pathogen when inoculated into newborn mice of particular H-2(k) strains. Using D(k) tetramers containing the dominant antipolyoma CD8(+) T cell epitope, middle T protein (MT)389-397, and intracellular interferon gamma staining, we enumerated MT389-specific CD8(+) T cells in infected neonates having opposite susceptibilities to polyoma virus-induced tumors. In resistant mice, MT389-specific CD8(+) T cells dramatically expanded during acute infection in neonates to a frequency rivaling that in adults; furthermore, in both neonatal and adult mice, this antipolyoma CD8(+) T cell response exhibited nearly identical T cell receptor (TCR) functional avidities and TCR functional fingerprints. Susceptible mice mounted an MT389-specific CD8(+) T cell response of only fourfold lower magnitude than resistant mice; but, in clear contrast to resistant mice, these CD8(+) T cells lacked ex vivo MT389-specific cytotoxic activity. However, MT389-specific CD8(+) T cells in resistant and susceptible mice expressed similar TCR avidities, perforin levels, and surface type O-glycan levels indicative of mature CD8(+) T cell effectors. Upon in vitro restimulation with infected antigen-presenting cells, CD8(+) T cells from acutely infected susceptible neonates acquired strong MT389-specific cytotoxicity. These findings indicate that polyoma-specific CD8(+) T cells are armed with, but restrained from deploying, their cytotoxic effector function in mice susceptible to polyoma virus tumorigenesis.

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Kinetic analysis of virus titers in newborn inoculated CBA/J mice. Spleens from neonatally infected mice were harvested, homogenized, and titered for polyoma virus by plaque assay. Each value represents the mean ± SD PFU/mg spleen from five to six individual mice. *, below detection limit of 1 PFU/mg.
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Figure 7: Kinetic analysis of virus titers in newborn inoculated CBA/J mice. Spleens from neonatally infected mice were harvested, homogenized, and titered for polyoma virus by plaque assay. Each value represents the mean ± SD PFU/mg spleen from five to six individual mice. *, below detection limit of 1 PFU/mg.

Mentions: CBA/J neonates were also considerably less efficient in eliminating infectious polyoma virus than C3H/HeN mice. Although splenic virus titers were equivalent at early stages of infection in neonatal mice of each strain, 8-d-old CBA/J mice possessed 10-fold higher levels of infectious virus in their spleens, with significant viral titers detected at least through day 23 after infection (Fig. 7). This higher peak and substantially longer sustained virus levels in neonatal CBA/J mice may, in fact, have also provided an antigenic stimulus to boost the size of the CBA/J memory CD8+ T cell pool, which was of nearly the same size as C3H/HeN neonates (Fig. 6).


Antiviral CD8+ T cell responses in neonatal mice: susceptibility to polyoma virus-induced tumors is associated with lack of cytotoxic function by viral antigen-specific T cells.

Moser JM, Altman JD, Lukacher AE - J. Exp. Med. (2001)

Kinetic analysis of virus titers in newborn inoculated CBA/J mice. Spleens from neonatally infected mice were harvested, homogenized, and titered for polyoma virus by plaque assay. Each value represents the mean ± SD PFU/mg spleen from five to six individual mice. *, below detection limit of 1 PFU/mg.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193393&req=5

Figure 7: Kinetic analysis of virus titers in newborn inoculated CBA/J mice. Spleens from neonatally infected mice were harvested, homogenized, and titered for polyoma virus by plaque assay. Each value represents the mean ± SD PFU/mg spleen from five to six individual mice. *, below detection limit of 1 PFU/mg.
Mentions: CBA/J neonates were also considerably less efficient in eliminating infectious polyoma virus than C3H/HeN mice. Although splenic virus titers were equivalent at early stages of infection in neonatal mice of each strain, 8-d-old CBA/J mice possessed 10-fold higher levels of infectious virus in their spleens, with significant viral titers detected at least through day 23 after infection (Fig. 7). This higher peak and substantially longer sustained virus levels in neonatal CBA/J mice may, in fact, have also provided an antigenic stimulus to boost the size of the CBA/J memory CD8+ T cell pool, which was of nearly the same size as C3H/HeN neonates (Fig. 6).

Bottom Line: Using D(k) tetramers containing the dominant antipolyoma CD8(+) T cell epitope, middle T protein (MT)389-397, and intracellular interferon gamma staining, we enumerated MT389-specific CD8(+) T cells in infected neonates having opposite susceptibilities to polyoma virus-induced tumors.Upon in vitro restimulation with infected antigen-presenting cells, CD8(+) T cells from acutely infected susceptible neonates acquired strong MT389-specific cytotoxicity.These findings indicate that polyoma-specific CD8(+) T cells are armed with, but restrained from deploying, their cytotoxic effector function in mice susceptible to polyoma virus tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Emory University School of Medicine, Wooodruff Memorial Research Building, 1639 Pierce Dr., Atlanta, Georgia 30322, USA.

ABSTRACT
Polyoma virus is a potent oncogenic pathogen when inoculated into newborn mice of particular H-2(k) strains. Using D(k) tetramers containing the dominant antipolyoma CD8(+) T cell epitope, middle T protein (MT)389-397, and intracellular interferon gamma staining, we enumerated MT389-specific CD8(+) T cells in infected neonates having opposite susceptibilities to polyoma virus-induced tumors. In resistant mice, MT389-specific CD8(+) T cells dramatically expanded during acute infection in neonates to a frequency rivaling that in adults; furthermore, in both neonatal and adult mice, this antipolyoma CD8(+) T cell response exhibited nearly identical T cell receptor (TCR) functional avidities and TCR functional fingerprints. Susceptible mice mounted an MT389-specific CD8(+) T cell response of only fourfold lower magnitude than resistant mice; but, in clear contrast to resistant mice, these CD8(+) T cells lacked ex vivo MT389-specific cytotoxic activity. However, MT389-specific CD8(+) T cells in resistant and susceptible mice expressed similar TCR avidities, perforin levels, and surface type O-glycan levels indicative of mature CD8(+) T cell effectors. Upon in vitro restimulation with infected antigen-presenting cells, CD8(+) T cells from acutely infected susceptible neonates acquired strong MT389-specific cytotoxicity. These findings indicate that polyoma-specific CD8(+) T cells are armed with, but restrained from deploying, their cytotoxic effector function in mice susceptible to polyoma virus tumorigenesis.

Show MeSH
Related in: MedlinePlus