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.
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.
Department of Pathology, Emory University School of Medicine, Wooodruff Memorial Research Building, 1639 Pierce Dr., Atlanta, Georgia 30322, USA.
J M
JM
Moser
J D
JD
Altman
A E
AE
Lukacher
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000952:Antigens, Polyomavirus Transforming / Q000276:immunology; D000957:Antigens, Viral, Tumor / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002460:Cell Line; D003601:Cytotoxicity Tests, Immunologic; D004198:Disease Susceptibility / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D007111:Immunity, Cellular / Q000276:immunology; D016056:Immunodominant Epitopes / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D008808:Mice, Inbred CBA; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000821:virology; D030361:Papillomavirus Infections / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011120:Polyomavirus / Q000276:immunology* / Q000472:pathogenicity; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014412:Tumor Virus Infections / Q000276:immunology
D000952:Antigens, Polyomavirus Transforming; D000957:Antigens, Viral, Tumor; D000939:Epitopes; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D007371:Interferon-gamma