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T cells and T cell tumors efficiently generate antigen-specific cytotoxic T cell immunity when modified with an NKT ligand.

Chung Y, Lee YH, Zhang Y, Martin-Orozco N, Yamazaki T, Zhou D, Kang CY, Hwu P, Kwak LW, Dong C - Oncoimmunology (2012)

Bottom Line: While T cells loaded with a class I-restricted peptide induced proliferation but not effector differentiation of antigen-specific CD8 T cells, injection of T cells co-pulsed with αGC strongly induced IFNγ and Granzyme B expression in T cells and complete lysis of target cells in vivo.Of note, the generation of this cytotoxic T cell response was independent of IL-4, IFNγ, IL-12, IL-21 and costimulation.Our data indicate that iNKT cell can license a non-professional APC to directly trigger antigen-specific cytotoxic T cell responses, which provides an alternative cellular vaccine strategy against tumors.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology; Center for Cancer Immunology Research; University of Texas MD Anderson Cancer Center; Houston, TX USA ; Institute of Molecular Medicine; University of Texas Medical School; Houston, TX USA.

ABSTRACT
Various Invariant NKT (iNKT) cell ligands have been shown as potent adjuvants in boosting T cell reactivates to antigens on professional APC. Non-professional APC, such as T cells, also co-expressing MHC class I and CD1d, have been unattractive cell vaccine carriers due to their poor immunogenicity. Here, we report that T cells as well as T cell lymphoma can efficiently generate antigen-specific cytotoxic T lymphocytes (CTL) responses in mice in vivo, when formulated to present iNKT ligand α-galactosylceramide (αGC) on their surface CD1d. Vaccination with αGC-pulsed EG-7 T-cell lymphoma induced tumor-specific CTL response and suppressed the growth of EG-7 in a CD8 T cell-dependent manner. Injection of αGC-loaded CD4 T cells in mice efficiently activated iNKT cells in vivo. While T cells loaded with a class I-restricted peptide induced proliferation but not effector differentiation of antigen-specific CD8 T cells, injection of T cells co-pulsed with αGC strongly induced IFNγ and Granzyme B expression in T cells and complete lysis of target cells in vivo. Presentation of αGC and peptide on the same cells was required for optimal CTL response and vaccinating T cells appeared to directly stimulate both iNKT and cytotoxic CD8 T cells. Of note, the generation of this cytotoxic T cell response was independent of IL-4, IFNγ, IL-12, IL-21 and costimulation. Our data indicate that iNKT cell can license a non-professional APC to directly trigger antigen-specific cytotoxic T cell responses, which provides an alternative cellular vaccine strategy against tumors.

No MeSH data available.


Related in: MedlinePlus

Figure 5. Vaccination with T cell-based vaccine generates protective immunity against L. monocytogenes infection and tumor challenge. C57BL/6 mice (n = 3 mice per group) were vaccinated with the indicated cellular vaccine (day 0) before they were challenged with 5 × 104 live L. monocytogenes expressing OVA (day 10). Three days after the bacterial challenge, bacterial burden in spleen and liver was measured (A). Data are a representative of three separate experiments. (B) C57BL/6 mice (n = 3 mice per group) were vaccinated with the indicated cellular vaccine (day 0). Ten days later, recipients were intravenously challenged with live 2 × 105 B16-OVA. Two weeks after the tumor challenge, tumor foci in the lung were measured. (C) PBMC was isolated in mice vaccinated with the indicated cellular vaccine and restimulated with SIINFEKL in the presence of Golgi-Plug for 5 h before intracellular staining of IFNγ. Data are mean ± SE *p < 0.05, **p < 0.01, ***p < 0.001 in comparison with non-treated (Nil) group. Data are representative of two separate experiments.
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Figure 5: Figure 5. Vaccination with T cell-based vaccine generates protective immunity against L. monocytogenes infection and tumor challenge. C57BL/6 mice (n = 3 mice per group) were vaccinated with the indicated cellular vaccine (day 0) before they were challenged with 5 × 104 live L. monocytogenes expressing OVA (day 10). Three days after the bacterial challenge, bacterial burden in spleen and liver was measured (A). Data are a representative of three separate experiments. (B) C57BL/6 mice (n = 3 mice per group) were vaccinated with the indicated cellular vaccine (day 0). Ten days later, recipients were intravenously challenged with live 2 × 105 B16-OVA. Two weeks after the tumor challenge, tumor foci in the lung were measured. (C) PBMC was isolated in mice vaccinated with the indicated cellular vaccine and restimulated with SIINFEKL in the presence of Golgi-Plug for 5 h before intracellular staining of IFNγ. Data are mean ± SE *p < 0.05, **p < 0.01, ***p < 0.001 in comparison with non-treated (Nil) group. Data are representative of two separate experiments.

Mentions: We next tested whether the cytotoxic T cell response generated by T/αGC/pep vaccination is effective enough in suppressing the growth of intracellular bacteria and tumor in an antigen-specific manner. We first employed L. monocytogenes infection model since clearance of this bacterium is largely dependent on CD8 T cell response. Mice were vaccinated with T/αGC, T/αGC/pep or peptide-pulsed dendritic cells (DC/pep) as a control. Ten days later, the vaccinated mice were i.v. injected with L. monocytogenes expressing OVA and the bacterial burden in the spleen and liver was measured. As expected, mice vaccinated with DC/pep showed significantly lower bacterial burden in both spleen and liver compared with non-vaccinated mice (Fig. 5A). Compared with non-vaccinated group, mice vaccinated with T/αGC showed slightly lower bacterial burden, especially in the liver. In contrast, mice vaccinated with T/αGC/pep also showed significantly lower bacterial burden in both organs, which is comparable to those of DC/pep-vaccinated mice (Fig. 5A).


T cells and T cell tumors efficiently generate antigen-specific cytotoxic T cell immunity when modified with an NKT ligand.

Chung Y, Lee YH, Zhang Y, Martin-Orozco N, Yamazaki T, Zhou D, Kang CY, Hwu P, Kwak LW, Dong C - Oncoimmunology (2012)

Figure 5. Vaccination with T cell-based vaccine generates protective immunity against L. monocytogenes infection and tumor challenge. C57BL/6 mice (n = 3 mice per group) were vaccinated with the indicated cellular vaccine (day 0) before they were challenged with 5 × 104 live L. monocytogenes expressing OVA (day 10). Three days after the bacterial challenge, bacterial burden in spleen and liver was measured (A). Data are a representative of three separate experiments. (B) C57BL/6 mice (n = 3 mice per group) were vaccinated with the indicated cellular vaccine (day 0). Ten days later, recipients were intravenously challenged with live 2 × 105 B16-OVA. Two weeks after the tumor challenge, tumor foci in the lung were measured. (C) PBMC was isolated in mice vaccinated with the indicated cellular vaccine and restimulated with SIINFEKL in the presence of Golgi-Plug for 5 h before intracellular staining of IFNγ. Data are mean ± SE *p < 0.05, **p < 0.01, ***p < 0.001 in comparison with non-treated (Nil) group. Data are representative of two separate experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3376985&req=5

Figure 5: Figure 5. Vaccination with T cell-based vaccine generates protective immunity against L. monocytogenes infection and tumor challenge. C57BL/6 mice (n = 3 mice per group) were vaccinated with the indicated cellular vaccine (day 0) before they were challenged with 5 × 104 live L. monocytogenes expressing OVA (day 10). Three days after the bacterial challenge, bacterial burden in spleen and liver was measured (A). Data are a representative of three separate experiments. (B) C57BL/6 mice (n = 3 mice per group) were vaccinated with the indicated cellular vaccine (day 0). Ten days later, recipients were intravenously challenged with live 2 × 105 B16-OVA. Two weeks after the tumor challenge, tumor foci in the lung were measured. (C) PBMC was isolated in mice vaccinated with the indicated cellular vaccine and restimulated with SIINFEKL in the presence of Golgi-Plug for 5 h before intracellular staining of IFNγ. Data are mean ± SE *p < 0.05, **p < 0.01, ***p < 0.001 in comparison with non-treated (Nil) group. Data are representative of two separate experiments.
Mentions: We next tested whether the cytotoxic T cell response generated by T/αGC/pep vaccination is effective enough in suppressing the growth of intracellular bacteria and tumor in an antigen-specific manner. We first employed L. monocytogenes infection model since clearance of this bacterium is largely dependent on CD8 T cell response. Mice were vaccinated with T/αGC, T/αGC/pep or peptide-pulsed dendritic cells (DC/pep) as a control. Ten days later, the vaccinated mice were i.v. injected with L. monocytogenes expressing OVA and the bacterial burden in the spleen and liver was measured. As expected, mice vaccinated with DC/pep showed significantly lower bacterial burden in both spleen and liver compared with non-vaccinated mice (Fig. 5A). Compared with non-vaccinated group, mice vaccinated with T/αGC showed slightly lower bacterial burden, especially in the liver. In contrast, mice vaccinated with T/αGC/pep also showed significantly lower bacterial burden in both organs, which is comparable to those of DC/pep-vaccinated mice (Fig. 5A).

Bottom Line: While T cells loaded with a class I-restricted peptide induced proliferation but not effector differentiation of antigen-specific CD8 T cells, injection of T cells co-pulsed with αGC strongly induced IFNγ and Granzyme B expression in T cells and complete lysis of target cells in vivo.Of note, the generation of this cytotoxic T cell response was independent of IL-4, IFNγ, IL-12, IL-21 and costimulation.Our data indicate that iNKT cell can license a non-professional APC to directly trigger antigen-specific cytotoxic T cell responses, which provides an alternative cellular vaccine strategy against tumors.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology; Center for Cancer Immunology Research; University of Texas MD Anderson Cancer Center; Houston, TX USA ; Institute of Molecular Medicine; University of Texas Medical School; Houston, TX USA.

ABSTRACT
Various Invariant NKT (iNKT) cell ligands have been shown as potent adjuvants in boosting T cell reactivates to antigens on professional APC. Non-professional APC, such as T cells, also co-expressing MHC class I and CD1d, have been unattractive cell vaccine carriers due to their poor immunogenicity. Here, we report that T cells as well as T cell lymphoma can efficiently generate antigen-specific cytotoxic T lymphocytes (CTL) responses in mice in vivo, when formulated to present iNKT ligand α-galactosylceramide (αGC) on their surface CD1d. Vaccination with αGC-pulsed EG-7 T-cell lymphoma induced tumor-specific CTL response and suppressed the growth of EG-7 in a CD8 T cell-dependent manner. Injection of αGC-loaded CD4 T cells in mice efficiently activated iNKT cells in vivo. While T cells loaded with a class I-restricted peptide induced proliferation but not effector differentiation of antigen-specific CD8 T cells, injection of T cells co-pulsed with αGC strongly induced IFNγ and Granzyme B expression in T cells and complete lysis of target cells in vivo. Presentation of αGC and peptide on the same cells was required for optimal CTL response and vaccinating T cells appeared to directly stimulate both iNKT and cytotoxic CD8 T cells. Of note, the generation of this cytotoxic T cell response was independent of IL-4, IFNγ, IL-12, IL-21 and costimulation. Our data indicate that iNKT cell can license a non-professional APC to directly trigger antigen-specific cytotoxic T cell responses, which provides an alternative cellular vaccine strategy against tumors.

No MeSH data available.


Related in: MedlinePlus