Vaccine‐Induced Th1‐Type Responses are Dominant over Th2‐Type Responses in the Short Term whereas Pre‐existing Th2 Responses are Dominant in the Longer Term

Fernando, Germain J. P.; Stewart, Trina J.; Tindle, Robert W.; Frazer, Ian H.

doi:10.1046/j.1365-3083.1998.00327.x

Cited by 38 publications

(24 citation statements)

References 41 publications

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“…Although we demonstrate in the current study that Th responses can be cross-reactive between different PV L1 proteins, as would be predicted by the Ͼ70% sequence homology between the different PV genotypes (50) and the relative promiscuity of MHC class II for Th peptides (32,51), the observed lack of cross-inhibition between VLPs suggests that the demonstrated T cell cross-reactivity between PV genotypes may be of little biological relevance for induction of regulatory T cells. This observation is of some importance, as prior immunity to one PV genotype, induced by infection or prophylactic vaccination, would frequently be present in subjects infected with an unrelated PV genotype, and clearance of the new PV infection is thought to depend on induction of appropriate cell-mediated immune responses to PV protein epitopes not shared between PV types.…”

Section: Discussioncontrasting

confidence: 59%

IL-10 Mediates Suppression of the CD8 T Cell IFN-γ Response to a Novel Viral Epitope in a Primed Host

Liu

Hardy

et al. 2003

The Journal of Immunology

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Priming to Ag can inhibit subsequent induction of an immune response to a new epitope incorporated into that Ag, a phenomenon referred to as original antigenic sin. In this study, we show that prior immunity to a virus capsid can inhibit subsequent induction of the IFN-γ effector T cell response to a novel CD8-restricted antigenic epitope associated with the virus capsid. Inhibition does not involve Ab to the virus capsid, as it is observed in animals lacking B cells. CD8-restricted virus-specific T cell responses are not required, as priming to virus without CTL induction is associated with inhibition. However, IL-10−/− mice, in contrast to IL-10+/+ mice, generate CD8 T cell and Ab responses to novel epitopes incorporated into a virus capsid, even when priming to the capsid has resulted in high titer Ab to the capsid. Furthermore, capsid-primed mice, unable to mount a response to a novel epitope in the capsid protein, are nevertheless able to respond to the same novel epitope delivered independently of the capsid. Thus, inhibition of responsiveness to a novel epitope in a virus-primed animal is a consequence of secretion of IL-10 in response to presented Ag, which inhibits local generation of new CD8 IFN-γ-secreting effector T cells. Induction of virus- or tumor Ag-specific CD8 effector T cells in the partially Ag-primed host may thus be facilitated by local neutralization of IL-10.

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Section: Discussioncontrasting

confidence: 59%

IL-10 Mediates Suppression of the CD8 T Cell IFN-γ Response to a Novel Viral Epitope in a Primed Host

Liu

Hardy

et al. 2003

The Journal of Immunology

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“…Serum antibodies including isotype-specific antibodies against HPV16E7 were measured by ELISA [35] and IFN-g levels in culture supernatants were assessed by capture ELISA [28] as previously described. Serum antibody titers were calculated as the highest dilution of post-immunization serum producing an absorbance value greater than three standard deviations above the absorbance value for pre-immunization serum from that group of mice.…”

Section: Generation Of E7-specific Tcr-b Transgenic Micementioning

confidence: 99%

Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4⁺CD25⁺ T cells

et al. 2009

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The role of thymic versus peripheral epithelium in the regulation of the antigen-specific CD8 T-cell repertoire is still largely unresolved. We generated TCR-b chain transgenic mice in which an increased frequency of peripheral CD8 T cells recognizes an epitope from a viral oncoprotein (HPV16E7) in the context of H-2D b MHC class I. When T cells from these mice developed through the thymus of mice expressing functional E7 protein from a keratin 14 promoter, no major perturbation to transgenic T-cell development in the thymus was observed in these double-transgenic mice. In contrast, peripheral CD8 T-cell responses in the single-transgenic, K14E7 mice, including those unrelated to E7 antigen, are reduced whereas CD4 T-cell responses and antibody production are unchanged in these mice. Peripheral non-responsiveness among CD8 T cells was mediated largely by CD4 1 CD25 1 T cells. This suggested that epithelium expressing HPV16E7 protein inducesTreg that specifically down-regulate CD8 T-cell responses in the periphery. This may have important consequences for the treatment of cervical pre-cancers and provides a model for understanding differential suppression of T and B lymphocyte subsets by Treg.Key words: Skin . Suppression . T cells . Thymus . Transgenic mice IntroductionT-cell development starts in the thymus, where lymphocytes expressing TCR recognize self-peptides bound to MHC class I. Immature T cells are either deleted if the affinity of interaction is high (negative selection) or retained for export to the periphery if the affinity is low (positive selection). Medullary epithelial cells and DC are thought to induce negative selection whereas cortical epithelial cells positively select the T-cell repertoire [1][2][3][4]. Evidence for the role of cortical epithelial cells in positive selection comes from studies of MHC expression driven from a keratin 14 (K14) promoter in otherwise MHC-deficient mice [5,6]. In contrast, expression of protein and peptide antigens in K14 1 thymic epithelium results in the deletion of antigen-specific CD8 T cells and the editing of the transgenic TCR [7][8][9]. Consequently, depending on the model, T cells are either positively selected or negatively selected after contact with thymic epithelium. HPV16E7 is one of the key oncogenes expressed during progression to cervical cancer: the protein is expressed in the epithelial cells of the cervix during human papillomavirus (HPV) infection and subsequent cancer development [10]. Given that mice cannot be naturally infected with HPV, human cervical cancer has been modeled in mice by transgenic expression of HPV16E7 leading to E7 expression in the thymus and peripheral epithelial sites, e.g. skin keratinocytes [11,12]. The first such K14E7 transgenic mice were generated on an FVB mouse 481background that failed to present the dominant CD8 T-cell peptide identified in the C57BL/6 background [12]. Subsequently, K14E7FVB Â C57 F1 mice were generated and shown to have poor CD8 T-cell responses that were attributable to the induction of per...

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“…CpG (ODN-1826) containing two CpG motifs (TCCATGACGTTCCT GACGTT) was synthesized by GeneWorks. A GST E7 protein was produced as described previously (14). Aluminum hydroxide gel (alum) was purchased from Superfos Biosector, and IFA was obtained from Sigma-Aldrich.…”

Section: Cell Lines Peptides and Absmentioning

confidence: 99%

“…For in vivo-neutralizing experiments, 0.5-1 mg of mAbs or of normal rat serum was administered i.p. Immunization with recombinant GST-E7 protein combined with IFA was performed as described previously (14). For depletion of CD25 ϩ T cells in vivo, 0.5 mg of mAb was administered i.p., and depletion efficacy was monitored by FACS analysis.…”

Section: Immunization Of Micementioning

confidence: 99%

“…Cells were held for 2 days at 37 o C, and supernatants were collected for cytokine measurement. [ 3 H]Thymidine was added to the culture plate for another 16 h, and T cell proliferation was assayed as described previously (14). In some experiments, CD4-enriched lymphocytes from mice immunized with L1VLPs or unrelated Ag were added for 18 h to CD11c ϩ cells exposed to VLPs.…”

Section: In Vitro Activation Of E7 Tcr Transgenic Cd8 ϩ T Cells By Apmentioning

confidence: 99%

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Overcoming Original Antigenic Sin to Generate New CD8 T Cell IFN-γ Responses in an Antigen-Experienced Host

Liu

Dyer

Leggatt

et al. 2006

The Journal of Immunology

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The failure to mount effective immunity to virus variants in a previously virus-infected host is known as original antigenic sin. We have previously shown that prior immunity to a virus capsid protein inhibits induction by immunization of an IFN-γ CD8+ T cell response to an epitope linked to the capsid protein. We now demonstrate that capsid protein-primed CD4+ T cells secrete IL-10 in response to capsid protein presented by dendritic cells, and deviate CD8+ T cells responding to a linked MHC class I-restricted epitope to reduce IFN-γ production. Neutralizing IL-10 while delivering further linked epitope, either in vitro or in vivo, restores induction by immunization of an Ag-specific IFN-γ response to the epitope. This finding demonstrates a strategy for overcoming inhibition of MHC class I epitopes upon immunization of a host already primed to Ag, which may facilitate immunotherapy for chronic viral infection or cancer.

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Vaccine‐Induced Th1‐Type Responses are Dominant over Th2‐Type Responses in the Short Term whereas Pre‐existing Th2 Responses are Dominant in the Longer Term

Cited by 38 publications

References 41 publications

IL-10 Mediates Suppression of the CD8 T Cell IFN-γ Response to a Novel Viral Epitope in a Primed Host

IL-10 Mediates Suppression of the CD8 T Cell IFN-γ Response to a Novel Viral Epitope in a Primed Host

Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4⁺CD25⁺ T cells

Overcoming Original Antigenic Sin to Generate New CD8 T Cell IFN-γ Responses in an Antigen-Experienced Host

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Vaccine‐Induced Th1‐Type Responses are Dominant over Th2‐Type Responses in the Short Term whereas Pre‐existing Th2 Responses are Dominant in the Longer Term

Cited by 38 publications

References 41 publications

IL-10 Mediates Suppression of the CD8 T Cell IFN-γ Response to a Novel Viral Epitope in a Primed Host

IL-10 Mediates Suppression of the CD8 T Cell IFN-γ Response to a Novel Viral Epitope in a Primed Host

Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4+CD25+ T cells

Overcoming Original Antigenic Sin to Generate New CD8 T Cell IFN-γ Responses in an Antigen-Experienced Host

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Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T‐cell suppression mediated by CD4⁺CD25⁺ T cells