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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 6. Peptide and αGC on the same T cells are required for the optimal priming of CTL by iNKT-mediated T cell vaccine. (A) C57BL/6 (WT) or CD1d−/− mice were vaccinated with T cells co-pulsed with αGC and SIINFEKL (1 × 106 per mouse). (B) T cells from WT or bm-1 mice were co-pulsed with αGC and SIINFEKL before being i.v. injected into WT mice. (C) C57BL/6 mice were vaccinated with T cells co-pulsed with αGC and SIINFEKL (1 × 106 per mouse) or ‘a combination of T cells pulsed with SIINFEKL and of T cells pulsed with αGC’ (1 × 106 each) or T cells pulsed with SIINFEKL plus free form of αGC (i.p.). CFSEhigh, peptide-pulsed target; CFSElow, peptide-unpulsed control. Data are a representative of at least two separate experiments.
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Figure 6: Figure 6. Peptide and αGC on the same T cells are required for the optimal priming of CTL by iNKT-mediated T cell vaccine. (A) C57BL/6 (WT) or CD1d−/− mice were vaccinated with T cells co-pulsed with αGC and SIINFEKL (1 × 106 per mouse). (B) T cells from WT or bm-1 mice were co-pulsed with αGC and SIINFEKL before being i.v. injected into WT mice. (C) C57BL/6 mice were vaccinated with T cells co-pulsed with αGC and SIINFEKL (1 × 106 per mouse) or ‘a combination of T cells pulsed with SIINFEKL and of T cells pulsed with αGC’ (1 × 106 each) or T cells pulsed with SIINFEKL plus free form of αGC (i.p.). CFSEhigh, peptide-pulsed target; CFSElow, peptide-unpulsed control. Data are a representative of at least two separate experiments.

Mentions: We next sought to elucidate the mode of action in the efficient induction of peptide-specific cytotoxicity during T/αGC/pep vaccination. When we vaccinated CD1d-deficient mice with T/αGC/pep, we did not observe peptide-specific cytotoxicity in our in vivo CTL assay (Fig. 6A). Therefore, the antigen-specific cytotoxicity elicited by T/αGC/pep requires iNKT cells in vivo.


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 6. Peptide and αGC on the same T cells are required for the optimal priming of CTL by iNKT-mediated T cell vaccine. (A) C57BL/6 (WT) or CD1d−/− mice were vaccinated with T cells co-pulsed with αGC and SIINFEKL (1 × 106 per mouse). (B) T cells from WT or bm-1 mice were co-pulsed with αGC and SIINFEKL before being i.v. injected into WT mice. (C) C57BL/6 mice were vaccinated with T cells co-pulsed with αGC and SIINFEKL (1 × 106 per mouse) or ‘a combination of T cells pulsed with SIINFEKL and of T cells pulsed with αGC’ (1 × 106 each) or T cells pulsed with SIINFEKL plus free form of αGC (i.p.). CFSEhigh, peptide-pulsed target; CFSElow, peptide-unpulsed control. Data are a representative of at least 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 6: Figure 6. Peptide and αGC on the same T cells are required for the optimal priming of CTL by iNKT-mediated T cell vaccine. (A) C57BL/6 (WT) or CD1d−/− mice were vaccinated with T cells co-pulsed with αGC and SIINFEKL (1 × 106 per mouse). (B) T cells from WT or bm-1 mice were co-pulsed with αGC and SIINFEKL before being i.v. injected into WT mice. (C) C57BL/6 mice were vaccinated with T cells co-pulsed with αGC and SIINFEKL (1 × 106 per mouse) or ‘a combination of T cells pulsed with SIINFEKL and of T cells pulsed with αGC’ (1 × 106 each) or T cells pulsed with SIINFEKL plus free form of αGC (i.p.). CFSEhigh, peptide-pulsed target; CFSElow, peptide-unpulsed control. Data are a representative of at least two separate experiments.
Mentions: We next sought to elucidate the mode of action in the efficient induction of peptide-specific cytotoxicity during T/αGC/pep vaccination. When we vaccinated CD1d-deficient mice with T/αGC/pep, we did not observe peptide-specific cytotoxicity in our in vivo CTL assay (Fig. 6A). Therefore, the antigen-specific cytotoxicity elicited by T/αGC/pep requires iNKT cells in vivo.

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