Quality of the transgene-specific CD8+ T cell response induced by adenoviral vector immunization is critically influenced by virus dose and route of vaccination

TY - JOUR

T1 - Quality of the transgene-specific CD8+ T cell response induced by adenoviral vector immunization is critically influenced by virus dose and route of vaccination

AU - Holst, Peter Johannes

AU - Ørskov, Cathrine

AU - Thomsen, Allan Randrup

AU - Christensen, Jan Pravsgaard

PY - 2010/4/15

Y1 - 2010/4/15

N2 - Adenoviral vectors have been widely used for experimental gene therapy and vaccination, yet there is a surprising lack of knowledge connecting the route and dose of adenovirus administration to the induced transgene-specific immune response. We have recently demonstrated polyfunctional CD8+ T cells and protective memory responses using adenoviral vectors, which seem to contrast with recent reports suggesting that an exhausted CD8+ T cell phenotype is induced by inoculation with adenoviral vectors. Accordingly, we investigated the route and dose interrelationship for transgene-specific CD8+ T cells using adenoviral vectors encoding β-galactosidase applied either s.c. or i.v. Irrespective of the route of inoculation, most of the adenoviral inoculum was found to disseminate systemically as the dose was raised beyond 109 particles. The number of transgene-specific CD8+ T cells correlated positively with dissemination, whereas the functional capacity of the generated T cells correlated inversely with vector dissemination. A comparison of the immune response to s.c. or i.v. administration at moderate doses revealed that inoculation by both routes induced a transient peak of IFN-γ-producing CD8+ T cells 2 to 3 wk postinfection, but following i.v. administration, these cells were only detected in the liver. Two to four months after systemic, but not peripheral, immunization, dysfunctional transgene-specific CD8+ T cells impaired in both cytokine production and important in vivo effector functions, accumulated in the spleen. These findings indicate that the localization of the adenoviral inoculum and not the total Ag load determines the quality of the CD8+ T cell response induced with adenoviral vaccines.

AB - Adenoviral vectors have been widely used for experimental gene therapy and vaccination, yet there is a surprising lack of knowledge connecting the route and dose of adenovirus administration to the induced transgene-specific immune response. We have recently demonstrated polyfunctional CD8+ T cells and protective memory responses using adenoviral vectors, which seem to contrast with recent reports suggesting that an exhausted CD8+ T cell phenotype is induced by inoculation with adenoviral vectors. Accordingly, we investigated the route and dose interrelationship for transgene-specific CD8+ T cells using adenoviral vectors encoding β-galactosidase applied either s.c. or i.v. Irrespective of the route of inoculation, most of the adenoviral inoculum was found to disseminate systemically as the dose was raised beyond 109 particles. The number of transgene-specific CD8+ T cells correlated positively with dissemination, whereas the functional capacity of the generated T cells correlated inversely with vector dissemination. A comparison of the immune response to s.c. or i.v. administration at moderate doses revealed that inoculation by both routes induced a transient peak of IFN-γ-producing CD8+ T cells 2 to 3 wk postinfection, but following i.v. administration, these cells were only detected in the liver. Two to four months after systemic, but not peripheral, immunization, dysfunctional transgene-specific CD8+ T cells impaired in both cytokine production and important in vivo effector functions, accumulated in the spleen. These findings indicate that the localization of the adenoviral inoculum and not the total Ag load determines the quality of the CD8+ T cell response induced with adenoviral vaccines.

U2 - 10.4049/jimmunol.0900537

DO - 10.4049/jimmunol.0900537

M3 - Journal article

C2 - 20212099

SN - 0022-1767

VL - 184

SP - 4431

EP - 4439

JO - Journal of Immunology

JF - Journal of Immunology

IS - 8

ER -