Plasmid DNA Vaccine-Elicited Cellular Immune Responses Limit In Vivo Vaccine Antigen Expression through Fas-Mediated Apoptosis

Greenland, John R.; Geiben, Ralf; Ghosh, Sharmistha; Pastor, William A.; Letvin, Norman L.

doi:10.4049/jimmunol.178.9.5652

Cited by 28 publications

(43 citation statements)

References 37 publications

(40 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Animal whole blood was used to perform a pentamer analysis to evaluate F-specific CD8 response. Similar to the previous outcome with DNA vaccine (22), our pentamer analysis (Supplemental Fig. 1) indicated, over 1 wk after the immunization, that high-level expression of luciferase corresponded to imperceptible F-specific CD8 + T cell response.…”

Section: Early In Vivo Ag Expression At Site Of Injectionsupporting

confidence: 85%

“…1A, 1B), but not luciferase alone, indicating that the nature of the Ag can affect expression kinetics at later time points after administration (from days 7 to 14). This is reminiscent of previous findings obtained with DNA vaccines suggesting that an adaptive immune response directed toward the foreign protein expressed can lead to immunemediated clearance of cells expressing the Ag (22).…”

Section: Early In Vivo Ag Expression At Site Of Injectionsupporting

confidence: 72%

See 1 more Smart Citation

Induction of an IFN-Mediated Antiviral Response by a Self-Amplifying RNA Vaccine: Implications for Vaccine Design

Pepini

Pulichino

Carsillo

et al. 2017

The Journal of Immunology

162

View full text Add to dashboard Cite

RNA-based vaccines have recently emerged as a promising alternative to the use of DNA-based and viral vector vaccines, in part because of the potential to simplify how vaccines are made and facilitate a rapid response to newly emerging infections. SAM vaccines are based on engineered self-amplifying mRNA (SAM) replicons encoding an Ag, and formulated with a synthetic delivery system, and they induce broad-based immune responses in preclinical animal models. In our study, in vivo imaging shows that after the immunization, SAM Ag expression has an initial gradual increase. Gene expression profiling in injection-site tissues from mice immunized with SAM-based vaccine revealed an early and robust induction of type I IFN and IFN-stimulated responses at the site of injection, concurrent with the preliminary reduced SAM Ag expression. This SAM vaccine-induced type I IFN response has the potential to provide an adjuvant effect on vaccine potency, or, conversely, it might establish a temporary state that limits the initial SAM-encoded Ag expression. To determine the role of the early type I IFN response, SAM vaccines were evaluated in IFN receptor knockout mice. Our data indicate that minimizing the early type I IFN responses may be a useful strategy to increase primary SAM expression and the resulting vaccine potency. RNA sequence modification, delivery optimization, or concurrent use of appropriate compounds might be some of the strategies to finalize this aim.

show abstract

Section: Early In Vivo Ag Expression At Site Of Injectionsupporting

confidence: 85%

Section: Early In Vivo Ag Expression At Site Of Injectionsupporting

confidence: 72%

Induction of an IFN-Mediated Antiviral Response by a Self-Amplifying RNA Vaccine: Implications for Vaccine Design

Pepini

Pulichino

Carsillo

et al. 2017

The Journal of Immunology

162

View full text Add to dashboard Cite

show abstract

“…In addition, we observed that vaccine antigen expression persists in Fas receptor knockout mice, suggesting a role in this process for T cell-mediated apoptosis via the Fas/FasL pathway. 3 Based on these data, we hypothesized that CD8 ϩ T cells mediated vaccine antigen clearance through Fas-dependent apoptosis. Alternatively, other studies have suggested that the limited antigen expression in this setting may be a result of antibody-dependent cell-mediated cytotoxicity or complement-mediated lysis.…”

Section: Introductionmentioning

confidence: 99%

CD4+ T lymphocytes mediate in vivo clearance of plasmid DNA vaccine antigen expression and potentiate CD8+ T-cell immune responses

Geiben-Lynn

Greenland

Frimpong-Boateng

et al. 2008

Blood

Self Cite

View full text Add to dashboard Cite

IntroductionPlasmid DNA vaccines are a promising modality for immunization against a variety of infectious agents because they are safe, readily scalable, and easy distributed. Plasmid DNA vaccine vectors can elicit CD8 ϩ cytotoxic T lymphocytes (CTLs), CD4 ϩ T helper cell immune responses, as well as humoral immune responses. Nonetheless, the utility of DNA immunogens has been limited by their failure to elicit sufficiently potent immune responses. 1 One potential explanation for the limited immunogenicity of plasmid DNA is that vaccine antigen expression is generated at only transient and at low levels. 1 Immune-mediated destruction of antigen-producing muscle fibers appears to play a significant role in limiting vaccine antigen expression. Clearance of antigen-expressing myocytes has been shown to be dependent both on the immunogenicity of the antigen and the presence of a functional immune system. 2,3 However, the cell types responsible for this destruction remain to be determined. We have shown that damping of plasmid DNA vaccine antigen expression in vivo occurs coincident with the emergence of major histocompatibility complex (MHC) class I-restricted T-cell responses. In addition, we observed that vaccine antigen expression persists in Fas receptor knockout mice, suggesting a role in this process for T cell-mediated apoptosis via the Fas/FasL pathway. 3 Based on these data, we hypothesized that CD8 ϩ T cells mediated vaccine antigen clearance through Fas-dependent apoptosis. Alternatively, other studies have suggested that the limited antigen expression in this setting may be a result of antibody-dependent cell-mediated cytotoxicity or complement-mediated lysis. 4 In addition to adaptive immune responses, innate immune responses, such as those mediated by macrophages and NK cells, have also been implicated as potential contributors to the destruction of antigenproducing myocytes. 5,6 In the present study, we investigated the cell types responsible for antigen clearance in plasmid DNA vaccinated mice. We used an In Vivo Imaging System (IVIS), which enabled us to measure antigen expression in vivo precisely, without serial killing of the animals. Using knockout (KO) mice and antibodydepletion experiments, we investigated the relative contribution of NK cells, macrophages, CD8 ϩ T cells, and CD4 ϩ T cells to the damping of antigen expression in vaccinated animals. Surprisingly, we observed that CD4 ϩ T cells were both necessary and sufficient to mediate plasmid DNA vaccine antigen clearance. These findings demonstrate a central role for CD4 ϩ T cells in vaccine antigen clearance. Methods Animals and immunizationsSix-to 8-week-old wild-type C57BL/6, C57BL/6.␤2 M KO, C57BL/ 6.MHC II KO, Rag1 KO, and NK-function-deficient beige mice (C57BL/6-Lyst bg7-9 ) were purchased from The Jackson Laboratory (Bar Harbor, ME). All animals were housed and maintained in accordance with the Guide for the Care and Use of Laboratory Animals, 10 and all studies and procedures were reviewed and approved by the Institutional Animal...

show abstract

“…Vectors and Immunization-The plasmid DNA-Luciferase (DNA-Luc) construct with the AL11-Gag tag was constructed as described previously (27). This vector contains the GL4.10 luciferase gene (Promega, Madison, WI) and the immunodominant H-2D b -restricted SIV-Gag AL11 epitope flanked by triple alanine spacers.…”

Section: Methodsmentioning

confidence: 99%

Non-classical Natural Killer T Cells Modulate Plasmid DNA Vaccine Antigen Expression and Vaccine-elicited Immune Responses by MCP-1 Secretion after Interaction with a β2-Microglobulin-independent CD1d

Geiben-Lynn

Greenland

Frimpong-Boateng

et al. 2009

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The magnitude and durability of a plasmid DNA vaccine-induced immune response is shaped by immune effector molecules at the site of vaccination. In the present study, we show that antigen expression is modified by type II NKT cells, after interaction with a ␤2-microglobulin-independent Plasmid DNA vaccine-induced T cell memory responses are potentiated by innate immune responses that are generated during the first days after vaccination (1). At that time Natural Killer (NK) 2 and Natural Killer T (NKT) cells are attracted to the site of vaccine administration (2). Investigation into the function of both cell types following vaccination is important because in diverse biologic settings the release of NK or NKT cell-associated cytokines and chemokines has been shown to modulate adaptive T cell and humoral immune responses. Responding quickly, these cells have the capacity to produce cytokines and chemokines that help B cells produce antibodies, induce macrophages to develop enhanced microbicidal activity, and recruit T cells, neutrophils, eosinophils, and basophils to sites of infection and inflammation (3-9).NK and NKT cells have distinct and complementary functions. NK cells can recognize and eliminate tumors and virusinfected cells (3-5). NKT cells participate in immune processes associated with self-tolerance, including tumor rejection (10, 11), suppression of anti-tumor responses (12), down-regulation of autoimmune inflammatory diseases (13), immune privilege (14), tolerance to allografts and xenografts (15-17), fetal-maternal tolerance (18), protection against graft-versus-host disease (19), and protection against pathogens such as Cryptococcus (20) and hepatitis B virus (21).NK and NKT cells recognize target cells using distinct receptors. NK cell effector function is regulated by a balance between opposing signals delivered by inhibitory and activating receptors. A number of surface molecules expressed by NK cells, including CD2, CD16, CD69, and DNAM-1 have been implicated in the triggering of NK cell-mediated cytotoxicity. Additionally, the activating counterparts of the MHC-specific receptor p50 and the CD94/NKG2C molecules trigger NK-mediated cytotoxicity against MHC class I-expressing target cells. MHC class I negative targets are lysed after recognition by the cytotoxicity receptors NKp46, NKp44,.The majority of NKT cells express the NK lineage-specific receptor NK1.1 (CD161) and secrete cytokines upon recognition of CD1d. CD1d can present lipids and glycolipids as well as peptides to NKT cells. Invariant NKT (iNKT) cells or type I NKT cells make use of a restricted TCR repertoire, using an invariant TCR V␣14-J␣281 rearrangement and a limited set of TCR V␤ segments, suggesting that they recognize a limited set of CD1d-associated ligands (8, 9). A second group of CD1d-reactive NKT cells, referred to as type II NKT cells, use a diverse TCR repertoire that allows them to recognize a diversity of ligands presented on CD1d (8).Because plasmid DNA antigen clearance has been shown to be ␤2m-independent (22),...

show abstract

Plasmid DNA Vaccine-Elicited Cellular Immune Responses Limit In Vivo Vaccine Antigen Expression through Fas-Mediated Apoptosis

Cited by 28 publications

References 37 publications

Induction of an IFN-Mediated Antiviral Response by a Self-Amplifying RNA Vaccine: Implications for Vaccine Design

Induction of an IFN-Mediated Antiviral Response by a Self-Amplifying RNA Vaccine: Implications for Vaccine Design

CD4+ T lymphocytes mediate in vivo clearance of plasmid DNA vaccine antigen expression and potentiate CD8+ T-cell immune responses

Non-classical Natural Killer T Cells Modulate Plasmid DNA Vaccine Antigen Expression and Vaccine-elicited Immune Responses by MCP-1 Secretion after Interaction with a β2-Microglobulin-independent CD1d

Contact Info

Product

Resources

About