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

Liu, Xiao Song; Dyer, Joanne; Leggatt, Graham R.; Fernando, Germain J. P.; Zhong, Jie; Thomas, Ranjeny; Frazer, Ian H.

doi:10.4049/jimmunol.177.5.2873

Cited by 29 publications

(27 citation statements)

References 41 publications

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“…27,28,34 Recently several novel mechanisms have been described that might influence booster efficacies. Liu et al 41 demonstrated that a booster immunization with viruslike-particles in which an MHC class I-restricted epitope of E7 was coupled to the viral capsids was inhibited by viral capsid-specific CD4 + T cells producing interleukin-10. The experiment described in Figure 8 suggests that this mechanism does not apply for the inhibition we observe, as E7-virosomes added to the pre-injection with SFVLacZ can overcome the inhibition.…”

Section: T-cell Competition Involved In Genetic Immunizationmentioning

confidence: 99%

Viral vector-based prime-boost immunization regimens: a possible involvement of T-cell competition

et al. 2007

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Vaccination with recombinant viral vectors may be impeded by preexisting vector-specific immunity or by vector-specific immunity induced during the priming immunization. It is assumed that virus-neutralizing antibodies represent the principal effector mechanism of vector-specific immunity, while killing of infected cells by vector-specific cytotoxic T lymphocytes (CTLs) has also been suggested. Using recombinant Semliki Forest virus (rSFV) expressing E6E7 antigen from human papillomavirus, we demonstrate that secondary immune responses against E6E7 are neither affected by vector-specific antibodies nor by CTL-mediated killing of infected cells. Instead, the presence of the antigen during the prime immunization appeared to be the main determinant for the boosting efficacy. After priming with rSFVeE6,7, a homologous booster stimulated the primed E6E7-specific CTL response and induced long-lasting memory. Passively transferred SFV-neutralizing antibodies did not inhibit E6E7-specific CTL responses, although transgene expression was strongly reduced under these conditions. Conversely, in mice primed with irrelevant rSFV, induction of E6E7-specific CTLs was inhibited presumably due to vectorspecific responses induced by the priming immunization. When during the priming with irrelevant rSFV, E7-protein was co-administered, the inhibitory effect of vector-specific immunity was abolished. These results suggest that, apart from vector-specific antibodies or killing of infected cells, T-cell competition may be involved in determining the efficacy of viral vector-based prime-boost immunization regimens.

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Section: T-cell Competition Involved In Genetic Immunizationmentioning

confidence: 99%

Viral vector-based prime-boost immunization regimens: a possible involvement of T-cell competition

et al. 2007

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“…Anti-IL-10 receptor (anti-IL-10R) hybridoma (1B1.3a) (10) was provided by Dr. Warwick Britton of Centenary Institute, University of Sydney and was maintained in RPMI 1640 (Invitrogen) with 10% FBS.…”

Section: Cell Lines Peptides and Absmentioning

confidence: 99%

“…Positive selection of mouse spleen CD11c ϩ cells has been described previously (10). In brief, C57 BL/6 or IFN-␥R Ϫ/Ϫ mouse spleens were held in 1 mg/ml Collagenase D (Roche Diagnostics) and 500 l of Collagenase D was injected into each spleen.…”

Section: Positive Selection Of Mouse Spleen Cd11cmentioning

confidence: 99%

“…Production of anti-IL-10 mAb has been described elsewhere (10). In brief, hybridoma cells were cultured in RPMI 1640 with 1% FBS for 72 h; supernatants were collected and passed through a Protein G column (SigmaAldrich) and eluted by running 100 mM glycine (Sigma-Aldrich) through the column.…”

Section: Cell Lines Peptides and Absmentioning

confidence: 99%

“…However, the same particles have proven ineffective at inducing therapeutic immunity when used to immunize patients with persisting HPV infection (8), suggesting that prior exposure to Ag can alter the hosts' ability to respond to these particles. We have established a mechanism for this observation in an animal model using papillomavirus capsid protein virus-like particles expressing an additional papillomavirus Ag, E7 (9,10). Immunization with L1-E7 virus-like particles induced E7 specific IFN-␥ secreting CD8 T cells in naive animals but not in animals already primed to L1.…”

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IFN-γ Promotes Generation of IL-10 Secreting CD4+ T Cells that Suppress Generation of CD8 Responses in an Antigen-Experienced Host

Liu

Leerberg²,

MacDonald³

et al. 2009

The Journal of Immunology

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Ags characterizing tumors or chronic viral infection are generally presented to the host immune system before specific immunotherapy is initiated, and consequent generation of regulatory CD4+ T cells can inhibit induction of desired effector CD8 T cell responses. IL-10 produced in response to ongoing Ag exposure inhibits generation of CD8 T cells in an Ag-experienced host. We now show that this IL-10 is produced by Ag experienced CD4+ glucocorticoid-induced tumor necrosis factor receptor+ T cells that also secrete IFN-γ upon antigenic stimulation, that IL-10 secretion by these cells is enhanced through IFN-γ signaling, and, unexpectedly, that IFN-γ signaling is required for inhibition of generation of Ag-specific CD8 T cell responses in an Ag-experienced host. Systemic inhibition of both IL-10 and IFN-γ at the time of immunization may therefore facilitate induction of effective immunotherapeutic responses against tumor specific and viral Ags.

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Recent progress in vaccination against human papillomavirus‐mediated cervical cancer

McKee

Bergot

Leggatt

2015

Reviews in Medical Virology

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It has been more than 7 years since the commercial introduction of highly successful vaccines protecting against highrisk human papillomavirus (HPV) subtypes and the development of cervical cancer. From an immune standpoint, the dependence of cervical cancer on viral infection has meant that HPV proteins can be targeted as strong tumour antigens leading to clearance of the infection and the subsequent protection from cancer. Commercially available vaccines consisting of the L1 capsid protein assembled as virus-like particles (VLPs) induce neutralising antibodies that deny access of the virus to cervical epithelial cells. While greater than 90% efficacy has been demonstrated at the completion of large phase III trials in young women, vaccine developers are now addressing broader issues such as efficacy in boys, longevity of the protection and inducing cross-reactive antibody for oncogenic, non-vaccine HPV strains. For women with existing HPV infection, the prophylactic vaccines provide little protection, and consequently, the need for therapeutic vaccines will continue into the future. Therapeutic vaccines targeting HPVE6 and E7 proteins are actively being pursued with new adjuvants and delivery vectors, combined with an improved knowledge of the tumour microenvironment, showing great promise. This review will focus on recent progress in prophylactic and therapeutic vaccine development and implementation since the publication of end of study data from phase III clinical trials between 2010 and 2012. Copyright © 2015 John Wiley & Sons, Ltd. INTRODUCTIONTargeting cancers for immunotherapy is often complicated by a lack of immunogenic tumour peptides. Mutated or overexpressed self-antigens are frequently the targets and invoke a generally low affinity/avidity T and B cell response. In contrast, the tight association between infection with HPV and cervical cancer means that foreign viral proteins encoded by HPV can provide the basis of either prophylactic or therapeutic cancer vaccines [1,2]. The natural course of anogenital HPV infection results in overwhelming clearance of the virus in 98% of individuals with an immune component suggested by the increased risk of HPV-associated cancers in immune-compromised organ transplant recipients [3,4]. However, HPV genotype-specific antibodies against the viral capsid proteins (L1 and L2) are produced at only low levels in about half the patients, can take close to a year to develop after natural infection and associate with higher viral loads in the cervix [5]. Thus, natural antibody may reflect the non-lytic, localised, intracellular nature of the infection leading to poor immunogenicity for immunoglobulin production and a greater emphasis on T-cell immunity for viral clearance. In contrast, prior immunization with HPV capsid proteins in animal studies induces high titres of antibody that are protective against challenge infection. Early studies in dogs demonstrated that prior immunization with L1 capsid protein could protect beagles from mucosal challenge with canine oral ...

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

Cited by 29 publications

References 41 publications

Viral vector-based prime-boost immunization regimens: a possible involvement of T-cell competition

Viral vector-based prime-boost immunization regimens: a possible involvement of T-cell competition

IFN-γ Promotes Generation of IL-10 Secreting CD4+ T Cells that Suppress Generation of CD8 Responses in an Antigen-Experienced Host

Recent progress in vaccination against human papillomavirus‐mediated cervical cancer

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