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Tgf-β1 produced by activated CD4(+) T Cells Antagonizes T Cell Surveillance of Tumor Development.

Donkor MK, Sarkar A, Li MO - Oncoimmunology (2012)

Bottom Line: TGFβ1 is a regulatory cytokine with a crucial function in the control of T cell tolerance to tumors.However, absence of TGFβ1 produced by activated CD4(+) T cells and Treg cells inhibited tumor growth, and protected mice from spontaneous prostate cancer.These findings suggest that TGFβ1 produced by activated CD4(+) T cells is a necessary requirement for tumor evasion from immunosurveillance.

View Article: PubMed Central - PubMed

Affiliation: Immunology Program; Memorial Sloan-Kettering Cancer Center; New York, NY USA.

ABSTRACT
TGFβ1 is a regulatory cytokine with a crucial function in the control of T cell tolerance to tumors. Our recent study revealed that T cell-produced TGFβ1 is essential for inhibiting cytotoxic T cell responses to tumors. However, the exact TGFβ1-producing T cell subset required for tumor immune evasion remains unknown. Here we showed that deletion of TGFβ1 from CD8(+) T cells or Foxp3(+) regulatory T (Treg) cells did not protect mice against transplanted tumors. However, absence of TGFβ1 produced by activated CD4(+) T cells and Treg cells inhibited tumor growth, and protected mice from spontaneous prostate cancer. These findings suggest that TGFβ1 produced by activated CD4(+) T cells is a necessary requirement for tumor evasion from immunosurveillance.

No MeSH data available.


Related in: MedlinePlus

Figure 3. Deficiency of TGF-β1 in activated CD4+ T cells and Treg cells inhibits tumor development (A) Tgfb1f/n-TRAMP and Tgfb1f/nTnfrsf4-cre-TRAMP mice were evaluated for tumor development at 8 months of age. The weights (Wt) of urogenital tracts (UG) normalized to body Wt ± s.e.m of Tgfb1f/n TRAMP (n = 4) and Tgfb1f/nTnfrsf4-cre TRAMP (n = 3) mice are shown. The p value between two groups of tumor burden is shown (Students t-test). *Depicts statistically significant difference. (B) Flow cytometric analysis examining the expression of interferon gamma (IFNγ), granzyme B (GzmB) and PD-1 proteins in CD4+ and CD8+ T cells in the draining lymph nodes and prostates of Tgfb1f/n TRAMP and Tgfb1f/nTnfrsf4cre-TRAMP mice. For IFNγ expression, T cells were re-stimulated in vitro for five hours with phorbol 12-myristate 13-acetate (PMA), ionomycin and GolgiStop. Representatives of two independent experiments are shown.
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Figure 3: Figure 3. Deficiency of TGF-β1 in activated CD4+ T cells and Treg cells inhibits tumor development (A) Tgfb1f/n-TRAMP and Tgfb1f/nTnfrsf4-cre-TRAMP mice were evaluated for tumor development at 8 months of age. The weights (Wt) of urogenital tracts (UG) normalized to body Wt ± s.e.m of Tgfb1f/n TRAMP (n = 4) and Tgfb1f/nTnfrsf4-cre TRAMP (n = 3) mice are shown. The p value between two groups of tumor burden is shown (Students t-test). *Depicts statistically significant difference. (B) Flow cytometric analysis examining the expression of interferon gamma (IFNγ), granzyme B (GzmB) and PD-1 proteins in CD4+ and CD8+ T cells in the draining lymph nodes and prostates of Tgfb1f/n TRAMP and Tgfb1f/nTnfrsf4cre-TRAMP mice. For IFNγ expression, T cells were re-stimulated in vitro for five hours with phorbol 12-myristate 13-acetate (PMA), ionomycin and GolgiStop. Representatives of two independent experiments are shown.

Mentions: Transplanted tumor-induced immune responses could be fundamentally different from those of spontaneous tumors.31 Thus we needed to further substantiate, in a more physiological way, the acquisition of antitumor immunity due to the absence of TGFβ1 derived from activated CD4+ T cells and Treg cells. To this end, we bred Tgfb1f/nTnfrsf4-cre mice to TRAMP mice to obtain Tgfb1f/nTnfrsf4cre-TRAMP mice. When evaluated at 8 mo of age, Tgfb1f/n Tnfrsf4cre-TRAMP mice had substantially lower tumor burden than Tgfb1f/n-TRAMP mice (Fig. 3A). Analogous to TRAMP mice with attenuated T cell TGF-β signaling and total T cell-specific deletion of TGFβ1,13 CD4+ and CD8+ T cells in Tgfb1f/n Tnfrsf4cre-TRAMP mice differentiated into producers of IFNγ in the tumor-draining lymph nodes (Fig. 3B). Compared with the tumor draining lymph nodes, the CD8+ T cells that migrated into the prostates further upregulated GzmB production in Tgfb1f/n Tnfrsf4cre-TRAMP mice compared with Tgfb1f/n-TRAMP controls (Fig. 3B). Because Tgfb1f/n Foxp3cre-TRAMP mice are not protected from tumor development,13 these findings suggest that the inhibition of T cell responses in TRAMP mice has a specific requirement for TGFβ1 produced by activated CD4+ T cells.


Tgf-β1 produced by activated CD4(+) T Cells Antagonizes T Cell Surveillance of Tumor Development.

Donkor MK, Sarkar A, Li MO - Oncoimmunology (2012)

Figure 3. Deficiency of TGF-β1 in activated CD4+ T cells and Treg cells inhibits tumor development (A) Tgfb1f/n-TRAMP and Tgfb1f/nTnfrsf4-cre-TRAMP mice were evaluated for tumor development at 8 months of age. The weights (Wt) of urogenital tracts (UG) normalized to body Wt ± s.e.m of Tgfb1f/n TRAMP (n = 4) and Tgfb1f/nTnfrsf4-cre TRAMP (n = 3) mice are shown. The p value between two groups of tumor burden is shown (Students t-test). *Depicts statistically significant difference. (B) Flow cytometric analysis examining the expression of interferon gamma (IFNγ), granzyme B (GzmB) and PD-1 proteins in CD4+ and CD8+ T cells in the draining lymph nodes and prostates of Tgfb1f/n TRAMP and Tgfb1f/nTnfrsf4cre-TRAMP mice. For IFNγ expression, T cells were re-stimulated in vitro for five hours with phorbol 12-myristate 13-acetate (PMA), ionomycin and GolgiStop. Representatives of two independent experiments are shown.
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Related In: Results  -  Collection

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Figure 3: Figure 3. Deficiency of TGF-β1 in activated CD4+ T cells and Treg cells inhibits tumor development (A) Tgfb1f/n-TRAMP and Tgfb1f/nTnfrsf4-cre-TRAMP mice were evaluated for tumor development at 8 months of age. The weights (Wt) of urogenital tracts (UG) normalized to body Wt ± s.e.m of Tgfb1f/n TRAMP (n = 4) and Tgfb1f/nTnfrsf4-cre TRAMP (n = 3) mice are shown. The p value between two groups of tumor burden is shown (Students t-test). *Depicts statistically significant difference. (B) Flow cytometric analysis examining the expression of interferon gamma (IFNγ), granzyme B (GzmB) and PD-1 proteins in CD4+ and CD8+ T cells in the draining lymph nodes and prostates of Tgfb1f/n TRAMP and Tgfb1f/nTnfrsf4cre-TRAMP mice. For IFNγ expression, T cells were re-stimulated in vitro for five hours with phorbol 12-myristate 13-acetate (PMA), ionomycin and GolgiStop. Representatives of two independent experiments are shown.
Mentions: Transplanted tumor-induced immune responses could be fundamentally different from those of spontaneous tumors.31 Thus we needed to further substantiate, in a more physiological way, the acquisition of antitumor immunity due to the absence of TGFβ1 derived from activated CD4+ T cells and Treg cells. To this end, we bred Tgfb1f/nTnfrsf4-cre mice to TRAMP mice to obtain Tgfb1f/nTnfrsf4cre-TRAMP mice. When evaluated at 8 mo of age, Tgfb1f/n Tnfrsf4cre-TRAMP mice had substantially lower tumor burden than Tgfb1f/n-TRAMP mice (Fig. 3A). Analogous to TRAMP mice with attenuated T cell TGF-β signaling and total T cell-specific deletion of TGFβ1,13 CD4+ and CD8+ T cells in Tgfb1f/n Tnfrsf4cre-TRAMP mice differentiated into producers of IFNγ in the tumor-draining lymph nodes (Fig. 3B). Compared with the tumor draining lymph nodes, the CD8+ T cells that migrated into the prostates further upregulated GzmB production in Tgfb1f/n Tnfrsf4cre-TRAMP mice compared with Tgfb1f/n-TRAMP controls (Fig. 3B). Because Tgfb1f/n Foxp3cre-TRAMP mice are not protected from tumor development,13 these findings suggest that the inhibition of T cell responses in TRAMP mice has a specific requirement for TGFβ1 produced by activated CD4+ T cells.

Bottom Line: TGFβ1 is a regulatory cytokine with a crucial function in the control of T cell tolerance to tumors.However, absence of TGFβ1 produced by activated CD4(+) T cells and Treg cells inhibited tumor growth, and protected mice from spontaneous prostate cancer.These findings suggest that TGFβ1 produced by activated CD4(+) T cells is a necessary requirement for tumor evasion from immunosurveillance.

View Article: PubMed Central - PubMed

Affiliation: Immunology Program; Memorial Sloan-Kettering Cancer Center; New York, NY USA.

ABSTRACT
TGFβ1 is a regulatory cytokine with a crucial function in the control of T cell tolerance to tumors. Our recent study revealed that T cell-produced TGFβ1 is essential for inhibiting cytotoxic T cell responses to tumors. However, the exact TGFβ1-producing T cell subset required for tumor immune evasion remains unknown. Here we showed that deletion of TGFβ1 from CD8(+) T cells or Foxp3(+) regulatory T (Treg) cells did not protect mice against transplanted tumors. However, absence of TGFβ1 produced by activated CD4(+) T cells and Treg cells inhibited tumor growth, and protected mice from spontaneous prostate cancer. These findings suggest that TGFβ1 produced by activated CD4(+) T cells is a necessary requirement for tumor evasion from immunosurveillance.

No MeSH data available.


Related in: MedlinePlus