Priming of T cells by exogenous antigen cross-presented on MHC class I molecules

Shen, Lianjun; Rock, Kenneth L.

doi:10.1016/j.coi.2005.11.003

Cited by 153 publications

(150 citation statements)

References 63 publications

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“…Although it remains to be seen whether these principles apply to full-length Ags, we have data that the SIINFEKL peptide-epitope fused to fragment C requires N-terminal processing and is dependent upon TAP (for its presentation and induction of CD8 ϩ T cell responses, J. S. Roddick, J. N. Radcliffe, F. S. Stevenson, and S. M. Thirdborough, manuscript in preparation). This parallels cross-presented full-length Ags (44) and suggests that the same principles will hold. The main conclusion is that an optimal DNA-based T cell vaccine should express large amounts of Ag as a single burst.…”

Section: Discussionsupporting

confidence: 56%

Prolonged Antigen Expression following DNA Vaccination Impairs Effector CD8+ T Cell Function and Memory Development

Radcliffe

Roddick

Stevenson

et al. 2007

The Journal of Immunology

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After priming, naive T cells undergo a program of expansion, contraction, and memory formation. Numerous studies have indicated that only a brief period of antigenic stimulation is required to fully commit CD8+ T cells to this program. Nonetheless, the persistence of Ag may modulate the eventual fate of CD8+ T cells. Using DNA delivery, we showed previously that direct presentation primes high levels of effector CD8+ T cells as compared with cross-presentation. One explanation now revealed is that prolonged cross-presentation limits effector cell expansion and function. To analyze this, we used a drug-responsive system to regulate Ag expression after DNA injection. Reducing expression to a single burst expanded greater numbers of peptide-specific effector CD8+ T cells than sustained Ag. Consequences for memory development were assessed after boosting and showed that, although persistent Ag maintained higher numbers of tetramer-positive CD8+ T cells, these expanded less (∼4-fold) than those induced by transient Ag expression (∼35-fold). Transient expression at priming therefore led to a net higher secondary response. In terms of vaccine design, we propose that the most effective DNA-based CD8+ T cell vaccines will be those that deliver a short burst of Ag.

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Section: Discussionsupporting

confidence: 56%

Prolonged Antigen Expression following DNA Vaccination Impairs Effector CD8+ T Cell Function and Memory Development

Radcliffe

Roddick

Stevenson

et al. 2007

The Journal of Immunology

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“…Induction of protective immune responses against viruses or tumors can be achieved via cross-priming [4][5][6]. In this study, we employed the LCMV infection model to study how crosspresentation of multiple epitopes translates when studying cross-priming.…”

Section: Discussionmentioning

confidence: 99%

“…The priming of CTL is initiated by BM-derived professional APC (pAPC) [1][2][3], and is achieved via endogenous ''direct-presentation'' and exogenous ''cross-presentation'' [4][5][6]. The contribution of multiple epitopes from viral proteins to the cross-presentation pathway after infections is not well understood.…”

Section: Introductionmentioning

confidence: 99%

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

et al. 2010

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The initiation of CD8 1 T cell (CTL) immune responses can occur via cross-priming. Recent data suggested a relationship between cross-presentation and immunodominance of epitope-specific T cells. To test this association, we evaluated the efficacy of crosspresentation for several virus epitopes in vitro and examined if this can be extrapolated in vivo. Employing lymphocytic choriomeningitis virus (LCMV), we demonstrate that the cross-presentation and cross-priming of LCMV antigens were dominated by NP396, but not NP205 when analyzing the LCMV-NP. Although with LCMV-GP, cross-presentation was dominated by GP276, and cross-priming was dominated by GP33. Importantly, although NP396 was significantly more efficient than GP33 in cross-presentation, cross-priming of their specific CTL was comparable. In a subsequent virus challenge after cross-priming, GP33-specific CTL dominated the response. Accordingly, based on our data, the ability of viral epitopes to be cross-presented in vitro does not entirely reflect what would occur in cross-priming. Thus, weak cross-presenting antigens may still cross-prime an efficient CTL response depending on other in vivo elements such as the naïve T-cell precursor frequencies.

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“…The allovaccine can be used in partially human leukocyte antigen (HLA)-matched patients, particularly when the HLA-restriction of immunogenic antigenic peptides is known, but it can also be used across HLA-barriers as cross-priming through autologous antigen-presenting cells is likely to occur. 17 We selected patients carrying the HLA-A*0201 allele for inclusion in this trial as the vaccine cells expressed this HLA allotype and extensive preclinical studies revealed that surrogate peptides presented by HLA-A2 molecules on RCC26 cells could be used for immune monitoring.…”

Section: Introductionmentioning

confidence: 99%

Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

et al. 2010

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Despite novel targeted agents, prognosis of metastatic renal cell cancer (RCC) remains poor, and experimental therapeutic strategies are warranted. Transfection of tumor cells with co-stimulatory molecules and/or cytokines is able to increase immunogenicity. Therefore, in our clinical study, 10 human leukocyte antigen (HLA)-A*0201 + patients with histologicallyconfirmed progressive metastatic clear cell RCC were immunized repetitively over 22 weeks with 2.5-40Â10 6 interleukin (IL)-7/CD80 cotransfected allogeneic HLA-A*0201 + tumor cells (RCC26/IL-7/CD80). Endpoints of the study were feasibility, safety, immunological and clinical responses. Vaccination was feasible and safe. In all, 50% of the patients showed stable disease throughout the study; the median time to progression was 18 weeks. However, vaccination with allogeneic RCC26/IL-7/ CD80 tumor cells was not able to induce TH1-polarized immune responses. A TH2 cytokine profile with increasing amounts of antigen-specific IL-10 secretion was observed in most of the responding patients. Interferon-g secretion by patient lymphocytes upon antigen-specific and non-specific stimulation was substantially impaired, both before and during vaccination, as compared with healthy controls. This is possibly due to profound tumor-induced immunosuppression, which may prevent induction of antitumor immune responses by the gene-modified vaccine. Vaccination in minimal residual disease with concurrent depletion of regulatory cells might be one strategy to overcome this limitation.

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Priming of T cells by exogenous antigen cross-presented on MHC class I molecules

Cited by 153 publications

References 63 publications

Prolonged Antigen Expression following DNA Vaccination Impairs Effector CD8+ T Cell Function and Memory Development

Prolonged Antigen Expression following DNA Vaccination Impairs Effector CD8+ T Cell Function and Memory Development

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

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