title: Early virus-associated bystander events affect the fitness of the CD8 T cell response to persistent virus infection.
abstract: Chronic Ag exposure during persistent viral infection erodes virus-specific CD8 T cell numbers and effector function, with a concomitant loss of pathogen control. Less clear are the respective contributions of Ag-specific and Ag-nonspecific (bystander) events on the quantity, quality, and maintenance of antiviral CD8 T cells responding to persistent virus infection. In this study, we show that low-dose inoculation with mouse polyomavirus (PyV) elicits a delayed, but numerically equivalent, antiviral CD8 T cell response compared with high-dose inoculation. Low-dose infection generated virus-specific CD8 T cells endowed with multicytokine functionality and a superior per cell capacity to produce IFN-gamma. PyV-specific CD8 T cells primed by low-dose inoculation also expressed higher levels of IL-7Ralpha and bcl-2 and possessed enhanced Ag-independent survival. Importantly, the quantity and quality of the antiviral CD8 T cell response elicited by dendritic cell-mediated immunization were mitigated by infection with a mutant PyV lacking the dominant CD8 T cell viral epitope. These findings suggest that the fitness of the CD8 T cell response to persistent virus infection is programmed in large part by early virus-associated Ag-nonspecific factors, and imply that limiting bystander inflammation at the time of inoculation, independent of Ag load, may optimize adaptive immunity to persistent viral infection.
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Nicolas P
authors.initials: NP
authors.lastname: Andrews
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Pack
authors.forename: Vaiva
authors.initials: V
authors.lastname: Vezys
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
authors.forename: Aron E
authors.initials: AE
authors.lastname: Lukacher
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D024201:Bystander Effect / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D007115:Immunization Schedule; D016130:Immunophenotyping; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011120:Polyomavirus / Q000235:genetics / Q000276:immunology*; D027601:Polyomavirus Infections / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D014412:Tumor Virus Infections / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control