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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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Regulatory T cells in lymph nodes: B6 mice were inoculated s.c. with 1 × 107 FBL-3 cells on day 0. a Numbers of CD4+Foxp3+ in drLNs and non-drLNs are shown. b Representative histograms display Foxp3 expression among CD4+ T cells in lymph nodes and tumor at day 6 ptc [Tumor-infiltrating lymphocytes (TILs)]. Numbers indicate percentages within the respective Foxp3+ gate. c Numbers of CD4+Foxp3+ T cells producing GzmB in lymph nodes are shown. Each dot represents an individual mouse, and the mean numbers are indicated by a line. The experiment was repeated three times with comparable results
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Fig3: Regulatory T cells in lymph nodes: B6 mice were inoculated s.c. with 1 × 107 FBL-3 cells on day 0. a Numbers of CD4+Foxp3+ in drLNs and non-drLNs are shown. b Representative histograms display Foxp3 expression among CD4+ T cells in lymph nodes and tumor at day 6 ptc [Tumor-infiltrating lymphocytes (TILs)]. Numbers indicate percentages within the respective Foxp3+ gate. c Numbers of CD4+Foxp3+ T cells producing GzmB in lymph nodes are shown. Each dot represents an individual mouse, and the mean numbers are indicated by a line. The experiment was repeated three times with comparable results

Mentions: Since Tregs were reported to have a suppressive role in the control of local tumor immune responses [6], we next assessed the significance of these cells in rejection of the FBL-3 tumor cells. To this end, the kinetics of Treg responses in drLN and non-drLN were compared. To distinguish between Treg and effector CD4+ T-cell populations, we utilized the unique Treg marker Foxp3. Interestingly, in non-drLN, the frequency of Foxp3+ Tregs started to increase at day 4 ptc and stayed elevated until day 20 ptc in comparison with naïve animals (Fig. 3a). In contrast, in drLN Treg, frequencies decreased on day 4 ptc and remained reduced until day 15 ptc. This was a surprising finding since we knew from previous studies in the FV model that Tregs expand at the side of inflammation during a chronic virus infection [16]. One possible explanation was that these cells leave the drLN and migrate into the tumor microenvironment. To address this, tumor-infiltrating lymphocytes (TIL) were isolated and examined for Treg frequencies. From the TIL, a mean of 38 % Tregs was found at 6 days ptc, whereas only a mean of 13 % Tregs was found in drLN, suggesting an infiltration of Tregs from the drLN into the tumor microenvironment.Fig. 3


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)

Regulatory T cells in lymph nodes: B6 mice were inoculated s.c. with 1 × 107 FBL-3 cells on day 0. a Numbers of CD4+Foxp3+ in drLNs and non-drLNs are shown. b Representative histograms display Foxp3 expression among CD4+ T cells in lymph nodes and tumor at day 6 ptc [Tumor-infiltrating lymphocytes (TILs)]. Numbers indicate percentages within the respective Foxp3+ gate. c Numbers of CD4+Foxp3+ T cells producing GzmB in lymph nodes are shown. Each dot represents an individual mouse, and the mean numbers are indicated by a line. The experiment was repeated three times with comparable results
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Related In: Results  -  Collection

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Fig3: Regulatory T cells in lymph nodes: B6 mice were inoculated s.c. with 1 × 107 FBL-3 cells on day 0. a Numbers of CD4+Foxp3+ in drLNs and non-drLNs are shown. b Representative histograms display Foxp3 expression among CD4+ T cells in lymph nodes and tumor at day 6 ptc [Tumor-infiltrating lymphocytes (TILs)]. Numbers indicate percentages within the respective Foxp3+ gate. c Numbers of CD4+Foxp3+ T cells producing GzmB in lymph nodes are shown. Each dot represents an individual mouse, and the mean numbers are indicated by a line. The experiment was repeated three times with comparable results
Mentions: Since Tregs were reported to have a suppressive role in the control of local tumor immune responses [6], we next assessed the significance of these cells in rejection of the FBL-3 tumor cells. To this end, the kinetics of Treg responses in drLN and non-drLN were compared. To distinguish between Treg and effector CD4+ T-cell populations, we utilized the unique Treg marker Foxp3. Interestingly, in non-drLN, the frequency of Foxp3+ Tregs started to increase at day 4 ptc and stayed elevated until day 20 ptc in comparison with naïve animals (Fig. 3a). In contrast, in drLN Treg, frequencies decreased on day 4 ptc and remained reduced until day 15 ptc. This was a surprising finding since we knew from previous studies in the FV model that Tregs expand at the side of inflammation during a chronic virus infection [16]. One possible explanation was that these cells leave the drLN and migrate into the tumor microenvironment. To address this, tumor-infiltrating lymphocytes (TIL) were isolated and examined for Treg frequencies. From the TIL, a mean of 38 % Tregs was found at 6 days ptc, whereas only a mean of 13 % Tregs was found in drLN, suggesting an infiltration of Tregs from the drLN into the tumor microenvironment.Fig. 3

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