Visualization of polyoma virus-specific CD8+ T cells in vivo during infection and tumor rejection.
T cells are critical for clearing infection and preventing tumors induced by polyoma virus, a natural murine papovavirus. We previously identified the immunodominant epitope for polyoma virus-specific CTL in tumor-resistant H-2k mice as the Dk-restricted peptide, MT389-397, derived from the polyoma middle T oncoprotein. In this study, we developed tetrameric Dk complexes containing the MT389-397 peptide to directly visualize and enumerate MT389-397-specific CTL during polyoma virus infection. We found that Dk/MT389 tetramer+CD8+ T cells undergo a massive expansion during primary infection such that by day 7 postinfection these Ag-specific CD8+ T cells constitute approximately 20% of the total and approximately 40% of the activated CD8+ T cells in the spleen. This expansion of Dk/MT389 tetramer+CD8+ T cells parallels the emergence of MT389-397-specific ex vivo cytolytic activity and clearance of polyoma virus. Notably, Dk/MT389 tetramer+CD8+ T cells are maintained in memory at very high levels. The frequencies of Dk/MT389 tetramer+CD8+ effector and memory T cells in vivo match those of CD8+ T cells producing intracellular IFN-gamma after 6-h in vitro stimulation by MT389-397 peptide. Consistent with preferential Vbeta6 expression by MT389-397-specific CD8+CTL lines and clones, Dk/MT389 tetramer+CD8+ T cells exhibit biased expression of this Vbeta gene segment. Finally, we show that Dk/MT389 tetramer+CD8+ T cells efficiently infiltrate a polyoma tumor challenge to virus-immune mice. Taken together, these findings strongly implicate virus-induced MT389-397-specific CD8+ T cells as essential effectors in eliminating polyoma-infected and polyoma-transformed cells in vivo.
Lukacher
A E
AE
Department of Pathology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA. alukach@emory.edu
Moser
J M
JM
Hadley
A
A
Altman
J D
JD
D000208:Acute Disease; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D006084:Graft Rejection / Q000276:immunology* / Q000821:virology; D007156:Immunologic Memory; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D030361:Papillomavirus Infections / Q000276:immunology* / Q000821:virology; D010446:Peptide Fragments / Q000276:immunology; D011120:Polyomavirus / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D014412:Tumor Virus Infections / Q000276:immunology* / Q000821:virology
D000952:Antigens, Polyomavirus Transforming; D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta