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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 7. Molecular requirements for efficient indication of CTL by iNKT-mediated T cell vaccine. (A) C57BL/6 mice (WT) or various cyokine-deficient mice with C57BL/6 background were vaccinated with T cells copulsed with αGC and SIINFEKL. (B) Pure CD4+ T cells were isolated from C57BL/6 (WT), B7−/−, B7h−/− or B7B7h−/− as described in Figure 1. Isolated T cells were co-pulsed with αGC and SIINFEKL ex vivo before injected into WT recipient. A week later, an in vivo CTL assay was performed. CFSEhigh, peptide-pulsed target; CFSElow, peptide-unpulsed control. Data are representative of three separate experiments.
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Figure 7: Figure 7. Molecular requirements for efficient indication of CTL by iNKT-mediated T cell vaccine. (A) C57BL/6 mice (WT) or various cyokine-deficient mice with C57BL/6 background were vaccinated with T cells copulsed with αGC and SIINFEKL. (B) Pure CD4+ T cells were isolated from C57BL/6 (WT), B7−/−, B7h−/− or B7B7h−/− as described in Figure 1. Isolated T cells were co-pulsed with αGC and SIINFEKL ex vivo before injected into WT recipient. A week later, an in vivo CTL assay was performed. CFSEhigh, peptide-pulsed target; CFSElow, peptide-unpulsed control. Data are representative of three separate experiments.

Mentions: Upon activation, iNKT cells promptly produce a wide range of cytokines including IL-4 and IFNγ. IL-4 produced by activated iNKT cells was shown to promote CD8 T cell proliferation.16 IFNγ and IL-12 produced upon iNKT and DC interaction mediate anti-tumor activity.17,18 Recent studies showed that IL-21 is produced by iNKT cells upon TcR stimulation and regulates the activation and expansion of iNKT cells.19,20 Therefore, we asked whether these cytokines produced after iNKT cell activation had any role in the generation of CTL in our T cell vaccine model. We vaccinated IL-4−/−, IFNγ−/−, IL-12 p35−/− or IL-21−/− mice with T/αGC/pep and performed in vivo CTL assay. As depicted in Figure 7A, we observed a complete peptide-specific CTL activity in all of cytokine-deficient mice we tested. Thus, none of these cytokines is necessary in the generation of CTL activity by the T cell vaccine.


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 7. Molecular requirements for efficient indication of CTL by iNKT-mediated T cell vaccine. (A) C57BL/6 mice (WT) or various cyokine-deficient mice with C57BL/6 background were vaccinated with T cells copulsed with αGC and SIINFEKL. (B) Pure CD4+ T cells were isolated from C57BL/6 (WT), B7−/−, B7h−/− or B7B7h−/− as described in Figure 1. Isolated T cells were co-pulsed with αGC and SIINFEKL ex vivo before injected into WT recipient. A week later, an in vivo CTL assay was performed. CFSEhigh, peptide-pulsed target; CFSElow, peptide-unpulsed control. Data are representative of three separate experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Figure 7. Molecular requirements for efficient indication of CTL by iNKT-mediated T cell vaccine. (A) C57BL/6 mice (WT) or various cyokine-deficient mice with C57BL/6 background were vaccinated with T cells copulsed with αGC and SIINFEKL. (B) Pure CD4+ T cells were isolated from C57BL/6 (WT), B7−/−, B7h−/− or B7B7h−/− as described in Figure 1. Isolated T cells were co-pulsed with αGC and SIINFEKL ex vivo before injected into WT recipient. A week later, an in vivo CTL assay was performed. CFSEhigh, peptide-pulsed target; CFSElow, peptide-unpulsed control. Data are representative of three separate experiments.
Mentions: Upon activation, iNKT cells promptly produce a wide range of cytokines including IL-4 and IFNγ. IL-4 produced by activated iNKT cells was shown to promote CD8 T cell proliferation.16 IFNγ and IL-12 produced upon iNKT and DC interaction mediate anti-tumor activity.17,18 Recent studies showed that IL-21 is produced by iNKT cells upon TcR stimulation and regulates the activation and expansion of iNKT cells.19,20 Therefore, we asked whether these cytokines produced after iNKT cell activation had any role in the generation of CTL in our T cell vaccine model. We vaccinated IL-4−/−, IFNγ−/−, IL-12 p35−/− or IL-21−/− mice with T/αGC/pep and performed in vivo CTL assay. As depicted in Figure 7A, we observed a complete peptide-specific CTL activity in all of cytokine-deficient mice we tested. Thus, none of these cytokines is necessary in the generation of CTL activity by the T cell vaccine.

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