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Tumor-specific CD4+ T cells develop cytotoxic activity and eliminate virus-induced tumor cells in the absence of regulatory T cells.

Akhmetzyanova I, Zelinskyy G, Schimmer S, Brandau S, Altenhoff P, Sparwasser T, Dittmer U - Cancer Immunol. Immunother. (2012)

Bottom Line: We show here that there is an expansion of tumor-specific CD4(+) T cells producing cytokines and cytotoxic molecule granzyme B (GzmB) in the early phase of tumor growth.Importantly, we demonstrate that in vivo depletion of regulatory T cells (Tregs) and CD8(+) T cells in FBL-3-bearing DEREG transgenic mice augments IL-2 and GzmB production by CD4(+) T cells and increases FV-specific CD4(+) T-cell effector and cytotoxic responses leading to the complete tumor regression.Therefore, the capacity to reject tumor acquired by tumor-reactive CD4(+) T cells largely depends on the direct suppressive activity of Tregs.

View Article: PubMed Central - PubMed

Affiliation: Institute for Virology, University of Duisburg-Essen, Virchowstr 179, 45147, Essen, Germany. ilseyar.akhmetzyanova@uni-due.de

ABSTRACT
The important role of tumor-specific cytotoxic CD8(+) T cells is well defined in the immune control of the tumors, but the role of effector CD4(+) T cells is poorly understood. In the current research, we have used a murine retrovirus-induced tumor cell line of C57BL/6 mouse origin, namely FBL-3 cells, as a model to study basic mechanisms of immunological control and escape during tumor formation. This study shows that tumor-specific CD4(+) T cells are able to protect against virus-induced tumor cells. We show here that there is an expansion of tumor-specific CD4(+) T cells producing cytokines and cytotoxic molecule granzyme B (GzmB) in the early phase of tumor growth. Importantly, we demonstrate that in vivo depletion of regulatory T cells (Tregs) and CD8(+) T cells in FBL-3-bearing DEREG transgenic mice augments IL-2 and GzmB production by CD4(+) T cells and increases FV-specific CD4(+) T-cell effector and cytotoxic responses leading to the complete tumor regression. Therefore, the capacity to reject tumor acquired by tumor-reactive CD4(+) T cells largely depends on the direct suppressive activity of Tregs. We suggest that a cytotoxic CD4(+) T-cell immune response may be induced to enhance resistance against oncovirus-associated tumors.

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The role of macrophages in FBL-3 tumor growth: DEREG mice were inoculated s.c. with 1 × 107 FBL-3 cells on day 0. One day before tumor inoculation, some mice also received DT to deplete Foxp3+ Tregs and day later monoclonal antibody to deplete CD8+ T cells. At day 6 post-tumor transplantation, leukocytes from drLNs and non-drLNs were analyzed. Numbers of CD11b+F4/80+ cells are shown (a). Numbers of CD11b+F4/80+CD86+ (b) and CD11b+TRAIL+ (c) cells are shown. Experiments were repeated twice with similar results. Differences between two groups are indicated (***P < 0.0005). The infiltration of CD4+ T cells and CD11b+ macrophages into the tumor is shown by immunohistology (d) (magnification ×200)
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Fig7: The role of macrophages in FBL-3 tumor growth: DEREG mice were inoculated s.c. with 1 × 107 FBL-3 cells on day 0. One day before tumor inoculation, some mice also received DT to deplete Foxp3+ Tregs and day later monoclonal antibody to deplete CD8+ T cells. At day 6 post-tumor transplantation, leukocytes from drLNs and non-drLNs were analyzed. Numbers of CD11b+F4/80+ cells are shown (a). Numbers of CD11b+F4/80+CD86+ (b) and CD11b+TRAIL+ (c) cells are shown. Experiments were repeated twice with similar results. Differences between two groups are indicated (***P < 0.0005). The infiltration of CD4+ T cells and CD11b+ macrophages into the tumor is shown by immunohistology (d) (magnification ×200)

Mentions: It is well known that macrophages can contribute to tumor rejection. We therefore focused our study on the role of these cells in FBL-3 tumor growth. Since tumor-bearing mice depleted for CD8+ T cells and Tregs showed complete tumor rejection, we analyzed in this group for CD11b+F4/80+ macrophage activation (expression of CD86 [28]) at day 6 ptc in lymph nodes in comparison with non-depleted and naïve animal. Significant expansion of CD11b+F4/80+ macrophages from drLNs but not in non-drLNs was observed (Fig. 7a). Depletion of CD8+ T cells and Tregs also promoted the upregulation of the costimulatory molecule CD86, which indicated macrophage activation (Fig. 7b). Interestingly, activated macrophages did not produce granzyme B (data not shown). However, significantly increased expression of the TNF-related apoptosis-inducing ligand (TRAIL) that can induce tumor cells apoptosis [29] was detected on macrophages from drLNs of mice depleted for CD8+ T cells and Tregs compared to non-depleted controls (Fig. 7c). These data were in line with the immunohistochemistry of tumors from the dual depleted group that showed infiltration of CD11b+ macrophages in the tumor mass in addition to CD4+ T-cell infiltration (Fig. 7d).Fig. 7


Tumor-specific CD4+ T cells develop cytotoxic activity and eliminate virus-induced tumor cells in the absence of regulatory T cells.

Akhmetzyanova I, Zelinskyy G, Schimmer S, Brandau S, Altenhoff P, Sparwasser T, Dittmer U - Cancer Immunol. Immunother. (2012)

The role of macrophages in FBL-3 tumor growth: DEREG mice were inoculated s.c. with 1 × 107 FBL-3 cells on day 0. One day before tumor inoculation, some mice also received DT to deplete Foxp3+ Tregs and day later monoclonal antibody to deplete CD8+ T cells. At day 6 post-tumor transplantation, leukocytes from drLNs and non-drLNs were analyzed. Numbers of CD11b+F4/80+ cells are shown (a). Numbers of CD11b+F4/80+CD86+ (b) and CD11b+TRAIL+ (c) cells are shown. Experiments were repeated twice with similar results. Differences between two groups are indicated (***P < 0.0005). The infiltration of CD4+ T cells and CD11b+ macrophages into the tumor is shown by immunohistology (d) (magnification ×200)
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Related In: Results  -  Collection

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Fig7: The role of macrophages in FBL-3 tumor growth: DEREG mice were inoculated s.c. with 1 × 107 FBL-3 cells on day 0. One day before tumor inoculation, some mice also received DT to deplete Foxp3+ Tregs and day later monoclonal antibody to deplete CD8+ T cells. At day 6 post-tumor transplantation, leukocytes from drLNs and non-drLNs were analyzed. Numbers of CD11b+F4/80+ cells are shown (a). Numbers of CD11b+F4/80+CD86+ (b) and CD11b+TRAIL+ (c) cells are shown. Experiments were repeated twice with similar results. Differences between two groups are indicated (***P < 0.0005). The infiltration of CD4+ T cells and CD11b+ macrophages into the tumor is shown by immunohistology (d) (magnification ×200)
Mentions: It is well known that macrophages can contribute to tumor rejection. We therefore focused our study on the role of these cells in FBL-3 tumor growth. Since tumor-bearing mice depleted for CD8+ T cells and Tregs showed complete tumor rejection, we analyzed in this group for CD11b+F4/80+ macrophage activation (expression of CD86 [28]) at day 6 ptc in lymph nodes in comparison with non-depleted and naïve animal. Significant expansion of CD11b+F4/80+ macrophages from drLNs but not in non-drLNs was observed (Fig. 7a). Depletion of CD8+ T cells and Tregs also promoted the upregulation of the costimulatory molecule CD86, which indicated macrophage activation (Fig. 7b). Interestingly, activated macrophages did not produce granzyme B (data not shown). However, significantly increased expression of the TNF-related apoptosis-inducing ligand (TRAIL) that can induce tumor cells apoptosis [29] was detected on macrophages from drLNs of mice depleted for CD8+ T cells and Tregs compared to non-depleted controls (Fig. 7c). These data were in line with the immunohistochemistry of tumors from the dual depleted group that showed infiltration of CD11b+ macrophages in the tumor mass in addition to CD4+ T-cell infiltration (Fig. 7d).Fig. 7

Bottom Line: We show here that there is an expansion of tumor-specific CD4(+) T cells producing cytokines and cytotoxic molecule granzyme B (GzmB) in the early phase of tumor growth.Importantly, we demonstrate that in vivo depletion of regulatory T cells (Tregs) and CD8(+) T cells in FBL-3-bearing DEREG transgenic mice augments IL-2 and GzmB production by CD4(+) T cells and increases FV-specific CD4(+) T-cell effector and cytotoxic responses leading to the complete tumor regression.Therefore, the capacity to reject tumor acquired by tumor-reactive CD4(+) T cells largely depends on the direct suppressive activity of Tregs.

View Article: PubMed Central - PubMed

Affiliation: Institute for Virology, University of Duisburg-Essen, Virchowstr 179, 45147, Essen, Germany. ilseyar.akhmetzyanova@uni-due.de

ABSTRACT
The important role of tumor-specific cytotoxic CD8(+) T cells is well defined in the immune control of the tumors, but the role of effector CD4(+) T cells is poorly understood. In the current research, we have used a murine retrovirus-induced tumor cell line of C57BL/6 mouse origin, namely FBL-3 cells, as a model to study basic mechanisms of immunological control and escape during tumor formation. This study shows that tumor-specific CD4(+) T cells are able to protect against virus-induced tumor cells. We show here that there is an expansion of tumor-specific CD4(+) T cells producing cytokines and cytotoxic molecule granzyme B (GzmB) in the early phase of tumor growth. Importantly, we demonstrate that in vivo depletion of regulatory T cells (Tregs) and CD8(+) T cells in FBL-3-bearing DEREG transgenic mice augments IL-2 and GzmB production by CD4(+) T cells and increases FV-specific CD4(+) T-cell effector and cytotoxic responses leading to the complete tumor regression. Therefore, the capacity to reject tumor acquired by tumor-reactive CD4(+) T cells largely depends on the direct suppressive activity of Tregs. We suggest that a cytotoxic CD4(+) T-cell immune response may be induced to enhance resistance against oncovirus-associated tumors.

Show MeSH
Related in: MedlinePlus