Limits...
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 2. CD8 T cells play a critical role in mediating antitumor activity. (A and B) C57BL/6 mice were vaccinated with EG-7/veh or EG-7/αGC on day -7 (n = 5 per group). EG-7/αGC vaccinated mice were intraperitoneally injected with CD8 depleting Ab (563.8) on day-3 and -1. On day 0, all mice were subcutaneously injected with 1 × 106 live EG-7 cells and the tumor volume (A) and the survival (B) were checked. *p < 0.01, **p < 0.005, p values were calculated with 2-way ANOVA (A) or Kaplan-Meier method (B) in comparison with EG-7/veh and EG-7/αGC+rIgG or EG-7/αGC+rIgG and EG-7/αGC+anti-CD8 group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3376985&req=5

Figure 2: Figure 2. CD8 T cells play a critical role in mediating antitumor activity. (A and B) C57BL/6 mice were vaccinated with EG-7/veh or EG-7/αGC on day -7 (n = 5 per group). EG-7/αGC vaccinated mice were intraperitoneally injected with CD8 depleting Ab (563.8) on day-3 and -1. On day 0, all mice were subcutaneously injected with 1 × 106 live EG-7 cells and the tumor volume (A) and the survival (B) were checked. *p < 0.01, **p < 0.005, p values were calculated with 2-way ANOVA (A) or Kaplan-Meier method (B) in comparison with EG-7/veh and EG-7/αGC+rIgG or EG-7/αGC+rIgG and EG-7/αGC+anti-CD8 group.

Mentions: Therefore, we next examined if the observed anti-tumor activity by vaccination with EG-7/αGC depends on CD8+ T cells. We injected anti-CD8 depleting antibody into the vaccinated mice before we transplanted live EG-7 cells into them. Depletion of CD8+ cells greatly decreased the protective anti-tumor activity by vaccination with EG-7/αGC (Fig. 2A) and the survival of vaccinated mice (Fig. 2B). Taken together, these results indicate that antitumor immunity generated by αGC-loaded EG-7 is, at least in part, mediated by CD8 T cells.


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 2. CD8 T cells play a critical role in mediating antitumor activity. (A and B) C57BL/6 mice were vaccinated with EG-7/veh or EG-7/αGC on day -7 (n = 5 per group). EG-7/αGC vaccinated mice were intraperitoneally injected with CD8 depleting Ab (563.8) on day-3 and -1. On day 0, all mice were subcutaneously injected with 1 × 106 live EG-7 cells and the tumor volume (A) and the survival (B) were checked. *p < 0.01, **p < 0.005, p values were calculated with 2-way ANOVA (A) or Kaplan-Meier method (B) in comparison with EG-7/veh and EG-7/αGC+rIgG or EG-7/αGC+rIgG and EG-7/αGC+anti-CD8 group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Figure 2. CD8 T cells play a critical role in mediating antitumor activity. (A and B) C57BL/6 mice were vaccinated with EG-7/veh or EG-7/αGC on day -7 (n = 5 per group). EG-7/αGC vaccinated mice were intraperitoneally injected with CD8 depleting Ab (563.8) on day-3 and -1. On day 0, all mice were subcutaneously injected with 1 × 106 live EG-7 cells and the tumor volume (A) and the survival (B) were checked. *p < 0.01, **p < 0.005, p values were calculated with 2-way ANOVA (A) or Kaplan-Meier method (B) in comparison with EG-7/veh and EG-7/αGC+rIgG or EG-7/αGC+rIgG and EG-7/αGC+anti-CD8 group.
Mentions: Therefore, we next examined if the observed anti-tumor activity by vaccination with EG-7/αGC depends on CD8+ T cells. We injected anti-CD8 depleting antibody into the vaccinated mice before we transplanted live EG-7 cells into them. Depletion of CD8+ cells greatly decreased the protective anti-tumor activity by vaccination with EG-7/αGC (Fig. 2A) and the survival of vaccinated mice (Fig. 2B). Taken together, these results indicate that antitumor immunity generated by αGC-loaded EG-7 is, at least in part, mediated by CD8 T cells.

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