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.
Moser
J M
JM
Department of Pathology, Emory University School of Medicine, Wooodruff Memorial Research Building, 1639 Pierce Dr., Atlanta, Georgia 30322, USA.
Altman
J D
JD
Lukacher
A E
AE
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