Autocrine transforming growth factor-ß1 promotes in vivo Th17 cell differentiation.

TGF-ß1 is a regulatory cytokine that has an important role in controlling T cell differentiation. T cell-produced TGF-ß1 acts on T cells to promote Th17 cell differentiation and the development of experimental autoimmune encephalomyelitis (EAE). However, the exact TGF-ß1-producing T cell subset required for Th17 cell generation and its cellular mechanism of action remain unknown. Here we showed that deletion of the Tgfb1 gene from activated T cells and Treg cells, but not Treg cells alone, abrogated Th17 cell differentiation, resulting in almost complete protection from EAE. Furthermore, differentiation of T cells both in vitro and in vivo demonstrated that TGF-ß1 was highly expressed by Th17 cells and acted in a predominantly autocrine manner to maintain Th17 cells in vivo. These findings reveal an essential role for activated T cell-produced TGF-ß1 in promoting the differentiation of Th17 cells and controlling inflammatory diseases.

T cell surveillance of oncogene-induced prostate cancer is impeded by T cell-derived TGF-ß1 cytokine.

Tolerance induction in T cells takes place in most tumors and is thought to account for tumor evasion from immune eradication. Production of the cytokine TGF-ß is implicated in immunosuppression, but the cellular mechanism by which TGF-ß induces T cell dysfunction remains unclear. With a transgenic model of prostate cancer, we showed that tumor development was not suppressed by the adaptive immune system, which was associated with heightened TGF-ß signaling in T cells from the tumor-draining lymph nodes. Blockade of TGF-ß signaling in T cells enhanced tumor antigen-specific T cell responses and inhibited tumor development. Surprisingly, T cell- but not Treg cell-specific ablation of TGF-ß1 was sufficient to augment T cell cytotoxic activity and blocked tumor growth and metastases. These findings reveal that T cell production of TGF-ß1 is an essential requirement for tumors to evade immunosurveillance independent of TGF-ß produced by tumors.

Tgf-ß1 produced by activated CD4(+) T Cells Antagonizes T Cell Surveillance of Tumor Development.

TGFß1 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 TGFß1 is essential for inhibiting cytotoxic T cell responses to tumors. However, the exact TGFß1-producing T cell subset required for tumor immune evasion remains unknown. Here we showed that deletion of TGFß1 from CD8(+) T cells or Foxp3(+) regulatory T (Treg) cells did not protect mice against transplanted tumors. However, absence of TGFß1 produced by activated CD4(+) T cells and Treg cells inhibited tumor growth, and protected mice from spontaneous prostate cancer. These findings suggest that TGFß1 produced by activated CD4(+) T cells is a necessary requirement for tumor evasion from immunosurveillance.

T cell- but not tumor cell-produced TGF-ß1 promotes the development of spontaneous mammary cancer.

During their development, tumors acquire multiple capabilities that enable them to proliferate, disseminate and evade immunosurveillance. A putative mechanism is through the production of the cytokine TGF-ß1. We showed in our recent studies that T cell-produced TGF-ß1 inhibits antitumor T cell responses to foster tumor growth raising the question of the precise function of TGF-ß1 produced by tumor cells in tumor development. Here, using a transgenic model of mammary cancer, we report that deletion of TGF-ß1 from tumor cells did not protect mice from tumor development. However, ablation of TGF-ß1 from T cells significantly inhibited mammary tumor growth. Additionally, absence of TGF-ß1 in T cells prevented tumors from advancing to higher pathological grades and further suppressed secondary tumor development in the lungs. These findings reveal T cells but not tumor cells as a critical source of TGF-ß1 that promotes tumor development.

Mammary tumor heterogeneity in the expansion of myeloid-derived suppressor cells.

The tumor microenvironment is heterogeneous for the expansion and infiltration by myeloid derived suppressor cells (MDSCs) which has been hypothesized to be dependent on tumor burden. We report a relationships between tumor size, MDSCs and T-cells; using four murine mammary tumors to assess tumor growth, infiltration and gene expression. Our analysis of cellular infiltration into tumors and gene expression used collagenase dissociated tumors and density gradient isolation of non-parenchymal cells (NPCs). The frequency of splenic and peripheral blood (PB) MDSCs was tumor dependent resulting in a significantly increased number of MDSCs. The MDSC frequency inversely correlated with the frequency of CD3+ lymphocytes in the spleen, independent of the tumor studied and directly correlated with tumor burden. Tumor growth up-regulated cyclooxygenase-2 (COX-2), vascular endothelial growth factor-A (VEGF-A), granulocyte (G-) and granulocyte-monocyte-colony stimulating factor (GM-CSF), arginase-1 (ARG-1), and nitric oxide synthase-2 (NOS-2) transcription in the tumor and spleens (not VEGF-A). The frequency of splenic MDSCs directly correlated with splenic COX-2, NOS-2, and ARG-1 message levels, while COX-2 and NOS-2 transcript levels inversely correlated with splenic CD3+ cell frequency. COX-2 mRNA levels also directly correlated with the ARG-1 and NOS-2 transcript levels from tumor-infiltrating leukocytic cells, supporting prostaglandin E2 as a regulator of ARG-1 and NOS-2 transcription. In summary, MDSC numbers in the spleen and tumor microenvironment are tumor dependent, directly correlating with tumor size and inversely correlating with T-cell number. MDSCs are also directly associated with VEGF-A and G-CSF transcript levels suggesting multiple mechanisms for MDSC regulation and COX-2, NOS-2 and ARG-1 supporting multiple mechanisms of T-cell suppression.