title: Comparison of human memory CD8 T cell responses to adenoviral early and late proteins in peripheral blood and lymphoid tissue.
abstract: Treatment of invasive adenovirus (Ad) disease in hematopoietic stem cell transplant (SCT) recipients with capsid protein hexon-specific donor T cells is under investigation. We propose that cytotoxic T cells (CTLs) targeted to the late protein hexon may be inefficient in vivo because the early Ad protein E3-19K downregulates HLA class I antigens in infected cells. In this study, CD8+ T cells targeted to highly conserved HLA A2-restricted epitopes from the early regulatory protein DNA polymerase (P-977) and late protein hexon (H-892) were compared in peripheral blood (PB) and tonsils of naturally infected adults. In tonsils, epitope-specific pentamers detected a significantly higher frequency of P-977+CD8+ T cells compared to H-892+CD8+ T cells; this trend was reversed in PB. Tonsil epitope-specific CD8+ T cells expressed IFN-γ and IL-2 but not perforin or TNF-α, whereas PB T cells were positive for IFN-γ, TNF-α, and perforin. Tonsil epitope-specific T cells expressed lymphoid homing marker CCR7 and exhibited lower levels of the activation marker CD25 but higher proliferative potential than PB T cells. Finally, in parallel with the kinetics of mRNA expression, P-977-specific CTLs lysed targets as early as 8 hrs post infection. In contrast, H-892-specific CTLs did not kill unless infected fibroblasts were pretreated with IFN-γ to up regulate HLA class I antigens, and cytotoxicity was delayed until 16-24 hours. These data show that, in contrast to hexon CTLs, central memory type DNA polymerase CTLs dominate the lymphoid compartment and kill fibroblasts earlier after infection without requiring exogenous IFN-γ. Thus, use of CTLs targeted to both early and late Ad proteins may improve the efficacy of immunotherapy for life-threatening Ad disease in SCT recipients.
authors.affiliation: Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Amita
authors.initials: A
authors.lastname: Joshi
authors.forename: Biwei
authors.initials: B
authors.lastname: Zhao
authors.forename: Cara
authors.initials: C
authors.lastname: Romanowski
authors.forename: David
authors.initials: D
authors.lastname: Rosen
authors.forename: Phyllis
authors.initials: P
authors.lastname: Flomenberg
mesh_terms: D017456:Adenovirus Early Proteins / Q000097:blood* / Q000276:immunology*; D000328:Adult; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D036022:Capsid Proteins / Q000097:blood* / Q000276:immunology*; D004259:DNA-Directed DNA Polymerase / Q000097:blood / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D007700:Kinetics; D014066:Palatine Tonsil / Q000378:metabolism*; D010641:Phenotype; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism
chemical_list: D017456:Adenovirus Early Proteins; D015415:Biomarkers; D036022:Capsid Proteins; D000939:Epitopes; C018315:hexon capsid protein, Adenovirus; D004259:DNA-Directed DNA Polymerase