The CD8+ T Cell Population Elicited by Recombinant Adenovirus Displays a Novel Partially Exhausted Phenotype Associated with Prolonged Antigen Presentation That Nonetheless Provides Long-Term Immunity

Abstract

We have previously reported that the CD8+ T cell response elicited by recombinant adenovirus vaccination displayed a delayed contraction in the spleen. In our current study, we demonstrate that this unusual kinetic is a general phenomenon observed in multiple tissues. Phenotypic analysis of transgene-specific CD8+ T cells present 30 days postimmunization with recombinant adenovirus revealed a population with evidence of partial exhaustion, suggesting that the cells had been chronically exposed to Ag. Although Ag expression could no longer be detected 3 wk after immunization, examination of Ag presentation within the draining lymph nodes demonstrated that APCs were loaded with Ag peptide for at least 40 days postimmunization, suggesting that Ag remains available to the system for a prolonged period, although the exact source of this Ag remains to be determined. At 60 days postimmunization, the CD8+ T cell population continued to exhibit a phenotype consistent with partially exhausted effector memory cells. Nonetheless, these CD8+ T cells conferred sterilizing immunity against virus challenge 7–12 wk postimmunization, suggesting that robust protective immunity can be provided by CD8+ T cells with an exhausted phenotype. These data demonstrate that prolonged exposure to Ag may not necessarily impair protective immunity and prompt a re-evaluation of the impact of persistent exposure to Ag on T cell function.

Quality of the Transgene-Specific CD8+ T Cell Response Induced by Adenoviral Vector Immunization Is Critically Influenced by Virus Dose and Route of Vaccination

“…In a number of studies, vaccination with adenoviral vectors has been found to induce strong and stable CD8 + T cell and Ab responses in mice, poultry, primates, and humans (2)(3)(4)(5)(6)(7)(8). Despite the wide application of adenoviral vectors, conflicting results have been observed using similar reagents in which the virus-induced CD8 + T cell population has been characterized as anything from exhausted (9) and chronically overactivated (10) to polyfunctional and long-lived (11,12). As the reports of induction of dysfunctional T cells contrast with our own data and clinical experience, we asked the question if differences in administration route and/or dosage might account for the observed discrepancies.…”

“…administration or peripheral overdosing shown in this study (9,10,39). The late i.v.-induced CD8 + T cells we observed bear all the markings of a dysfunctional T cell population: lower fraction of cytokine-producing cells out of total specific cells, lower IFN-g MFI, lower fraction of cells coproducing TNF-a or IL-2 and IFN-g, lower expression of IL-7R (CD127), absence of a contraction phase normally suggestive of a memory response, and an impaired ability to migrate into tissues and exert effector functions.…”

Recombinant lentivector as a genetic immunization vehicle for antitumor immunity

“…We observed significant OT-I proliferation in vivo three weeks after immunization with OVA expressing lentivector 46 . Similar prolonged Ag presentation was also reported following adenoviral vector immunization 79 . Importantly, this prolonged Ag exposure correlated with potent protective immunity and in general did not prevent recall responses 16,46,59,79,80 , even though partially exhausted effector memory T cell phenotype was observed in some cases 79 .…”

“…Similar prolonged Ag presentation was also reported following adenoviral vector immunization 79 . Importantly, this prolonged Ag exposure correlated with potent protective immunity and in general did not prevent recall responses 16,46,59,79,80 , even though partially exhausted effector memory T cell phenotype was observed in some cases 79 . It seems that the effect of prolonged Ag presentation on induced T cell responses after recombinant viral vector immunization is different from that observed in chronic viral infections where exhausted T cell responses were reported 77,81 .…”

High-dose chemotherapy augments the efficacy of recombinant adenovirus vaccines and improves the therapeutic outcome

“…The rAd vectors were propagated using 293 cells and purified using CsCl gradient centrifugation as described previously. 45 AdhDCT encodes the full-length human DCT (also known as TRP-2), 15 AdLCMV GP expresses the sequence corresponding to residues 33-41 and 61-80 of the lymphocytic choriomeningitis virus glycoprotein. AdLacZ expresses b-galactosidase as a transgene and was used as a negative control.…”