CpG motifs of DNA vaccines induce the expression of chemokines and MHC class II molecules on myocytes

Stan, Alexandru C.; Casares, Sofía; Brumeanu, Teodor‐D.; Klinman, Dennis M.; Bona, Constantin A.

doi:10.1002/1521-4141(200101)31:1<301::aid-immu301>3.0.co;2-k

Cited by 42 publications

(17 citation statements)

References 41 publications

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“…23 Thus far, it is not clear whether direct antigen presentation of myocytes to T cells, direct antigen presentation of professional antigen-presenting cells to T cells, or cross-priming is the most important mechanism to achieve a strong T-cell immune response. [23][24][25][26][27][28] Although it has been demonstrated that myocytes can present MHC class II molecules, 26,27 our data suggest that direct antigen presentation through myocytes to CD4 ϩ T cells might offer an important interaction to manipulate to improve DNA-induced T-cell immune responses. It is, however, possible that the importance of CD4 ϩ T cells in vaccine antigen clearance might not be seen for all antigens.…”

Section: Fasl-mediates Apoptosis Of Myocytes 4589mentioning

confidence: 74%

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

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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...

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Section: Fasl-mediates Apoptosis Of Myocytes 4589mentioning

confidence: 74%

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

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“…As pCMV-LIMPII has been designed to target peptides to lysosomes, direct transfection of APCs would be an efficient way to present peptides to 2.5mi + T cells. However, murine as well as human myocytes have been shown to express MHC class II molecules upon DNA uptake and to process Ag, which is dependent on IFN-g (33)(34)(35). Accumulation of myocytes transfected with the 2.5mi coding plasmid together with locally transfected APCs may be responsible for presenting the peptide to primed 2.5mi + T cells.…”

Section: Discussionmentioning

confidence: 99%

Targeting of a T Cell Agonist Peptide to Lysosomes by DNA Vaccination Induces Tolerance in the Nonobese Diabetic Mouse

Rivas

Driver

Garabatos

et al. 2011

The Journal of Immunology

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CD4 T cells are crucial effectors in the pathology of type 1 diabetes (T1D). Successful therapeutic interventions for prevention and cure of T1D in humans are still elusive. Recent research efforts have focused on the manipulation of T cells by treatment with DNA. In this paper, we studied the effects of a DNA treatment strategy designed to target antigenic peptides to the lysosomal compartment on a monospecific T cell population termed 2.5mi+ T cells that shares reactivity with the diabetogenic T cell clone BDC-2.5 in the NOD mouse. MHC class II tetramer analysis showed that repeated administrations were necessary to expand 2.5mi+ T cells in vivo. This expansion was independent of Ag presentation by B cells. A single peptide epitope was sufficient to induce protection against T1D, which was not due to Ag-specific T cell anergy. Typical Th2 cytokines such as IL-10 or IL-4 were undetectable in 2.5mi+ T cells, arguing against a mechanism of immune deviation. Instead, the expanded 2.5mi+ T cell population produced IFN-γ similar to 2.5mi+ T cells from naive mice. Protection against T1D by DNA treatment was completely lost in NOD.CD28−/− mice which are largely deficient of natural regulatory T cells (Treg). Although Ag-specific Foxp3+ Treg did not expand in response to DNA treatment, diabetes onset was delayed in Treg-reconstituted and DNA-treated NOD.SCID mice. These observations provide evidence for a Treg-mediated protective mechanism that is independent of the expansion or de novo generation of Ag-specific Treg.

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“…Muscle tissue possesses a unique function as a nonprofessional APC that can effectively stimulate both CD4 + and CD8 + T cells to survive, proliferate, and acquire effector function (13,14). To assess the ability of AAVrh32.33 and AAV8 to induce MHC II expression on skeletal muscle, gastrocnemius cryosections from WT and Tlr9-KO mice that received i.m.…”

Section: Figurementioning

confidence: 99%

“…TLR9 signaling can lead to the production of inflammatory cytokines IL-6, TNF-α, type I IFNs, and IL-1β, initiating both innate and adaptive immune responses (12). In addition, CpG motifs have been demonstrated to induce chemokines, MHC II molecules, and costimulatory ligands on myocytes, which have been postulated to act as nonprofessional APCs (13,14).…”

Section: Introductionmentioning

confidence: 99%

CpG-depleted adeno-associated virus vectors evade immune detection

Faust¹,

Bell²,

Cutler³

et al. 2013

J. Clin. Invest.

195

164

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CpG motifs of DNA vaccines induce the expression of chemokines and MHC class II molecules on myocytes

Cited by 42 publications

References 41 publications

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

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

Targeting of a T Cell Agonist Peptide to Lysosomes by DNA Vaccination Induces Tolerance in the Nonobese Diabetic Mouse

CpG-depleted adeno-associated virus vectors evade immune detection

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