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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 4. Model of TGFβ-mediated inhibition of antitumor T cell response. In the tumor-draining lymph nodes, CD4+ T cells become activated in response to tumor-associated antigens. Activated CD4+ T cells in the tumor draining lymph nodes secrete TGFβ1 that suppresses the activation, proliferation and differentiation of naïve tumor-specific CD8+ T cells into IFNγ-secreting T cells. Consequently, activated CD8+ T cells that migrate to the tumor site as effectors fail to elaborate CTL functions including GzmB expression. In addition, effector CD4+ T cells at the tumor site might also produce TGFβ1 to suppress the effector activities of CD8+ T cells. The net result is CTL dysfunction, which allows tumors to grow.
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Figure 4: Figure 4. Model of TGFβ-mediated inhibition of antitumor T cell response. In the tumor-draining lymph nodes, CD4+ T cells become activated in response to tumor-associated antigens. Activated CD4+ T cells in the tumor draining lymph nodes secrete TGFβ1 that suppresses the activation, proliferation and differentiation of naïve tumor-specific CD8+ T cells into IFNγ-secreting T cells. Consequently, activated CD8+ T cells that migrate to the tumor site as effectors fail to elaborate CTL functions including GzmB expression. In addition, effector CD4+ T cells at the tumor site might also produce TGFβ1 to suppress the effector activities of CD8+ T cells. The net result is CTL dysfunction, which allows tumors to grow.

Mentions: T cell tolerance could occur anywhere between the tumor-draining lymph nodes, where naïve tumor-specific T cells are primed, and the tumor sites after T cell infiltration. In the current view, TGFβ is thought to exert its suppressive effects on T cells at the effector phase. Once at the tumor site, T cells experience large quantities of TGFβ secreted by tumors that render T cells ineffective at killing target cells. This notion has held sway partly because it is an appealing model although direct evidence for it is lacking. In our recent findings, we provided an alternative mechanistic insight into TGFβ-mediated negative regulation of T cell responses to tumors (Fig. 4). We showed that tumor development triggered substantially higher phosphorylation of Smad2 and Smad3 in the tumor draining lymph nodes of 8-mo-old TRAMP mice than in other tissues including the tumor.13 This was an intriguing finding and it revealed that higher T cell TGFβ signaling is coincident with T cell priming to tumor antigens. By attenuating T cell intrinsic TGFβ signaling using DNR-TRAMP mice and deleting T cell TGF-β1 using Tgfb1f/nCd4cre-TRAMP (TKO-TRAMP) mice, we inhibited T cell Smad phosphorylation in the tumor-draining lymph nodes resulting in blockade of tumor development.13


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

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

Figure 4. Model of TGFβ-mediated inhibition of antitumor T cell response. In the tumor-draining lymph nodes, CD4+ T cells become activated in response to tumor-associated antigens. Activated CD4+ T cells in the tumor draining lymph nodes secrete TGFβ1 that suppresses the activation, proliferation and differentiation of naïve tumor-specific CD8+ T cells into IFNγ-secreting T cells. Consequently, activated CD8+ T cells that migrate to the tumor site as effectors fail to elaborate CTL functions including GzmB expression. In addition, effector CD4+ T cells at the tumor site might also produce TGFβ1 to suppress the effector activities of CD8+ T cells. The net result is CTL dysfunction, which allows tumors to grow.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376999&req=5

Figure 4: Figure 4. Model of TGFβ-mediated inhibition of antitumor T cell response. In the tumor-draining lymph nodes, CD4+ T cells become activated in response to tumor-associated antigens. Activated CD4+ T cells in the tumor draining lymph nodes secrete TGFβ1 that suppresses the activation, proliferation and differentiation of naïve tumor-specific CD8+ T cells into IFNγ-secreting T cells. Consequently, activated CD8+ T cells that migrate to the tumor site as effectors fail to elaborate CTL functions including GzmB expression. In addition, effector CD4+ T cells at the tumor site might also produce TGFβ1 to suppress the effector activities of CD8+ T cells. The net result is CTL dysfunction, which allows tumors to grow.
Mentions: T cell tolerance could occur anywhere between the tumor-draining lymph nodes, where naïve tumor-specific T cells are primed, and the tumor sites after T cell infiltration. In the current view, TGFβ is thought to exert its suppressive effects on T cells at the effector phase. Once at the tumor site, T cells experience large quantities of TGFβ secreted by tumors that render T cells ineffective at killing target cells. This notion has held sway partly because it is an appealing model although direct evidence for it is lacking. In our recent findings, we provided an alternative mechanistic insight into TGFβ-mediated negative regulation of T cell responses to tumors (Fig. 4). We showed that tumor development triggered substantially higher phosphorylation of Smad2 and Smad3 in the tumor draining lymph nodes of 8-mo-old TRAMP mice than in other tissues including the tumor.13 This was an intriguing finding and it revealed that higher T cell TGFβ signaling is coincident with T cell priming to tumor antigens. By attenuating T cell intrinsic TGFβ signaling using DNR-TRAMP mice and deleting T cell TGF-β1 using Tgfb1f/nCd4cre-TRAMP (TKO-TRAMP) mice, we inhibited T cell Smad phosphorylation in the tumor-draining lymph nodes resulting in blockade of tumor development.13

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