TGF-β

TGF-β superfamily is a family of structurally related proteins which includes TGF-β, activins/inhibins, and bone morphogenic proteins (BMPs). Members of the TGF-β superfamily regulate cellular functions such as proliferation, apoptosis, differentiation, and migration and thus play key roles in organismal development.

Fig.1 Synthesis and activation of TGF-β. (Tirado-Rodriguez, 2014)

TGF-β and γδ T Cell

Human Vδ2 expressing γδ T cells exerts potent cytotoxicity towards a variety of solid tumor and leukemia/lymphoma target cells. TGF-β unexpectedly augments the cytotoxic effector activity of short-term expanded Vδ2 T cells when purified γδ T cells are activated with specific pyrophosphate antigens and interleukin 2 (IL-2) or interleukin 15 (IL-15) in the presence of TGF-β. TGF-β up-regulates the expression of CD54, CD103, interferon-γ, interleukin 9 (IL-9) and granzyme B in γδ T cells while CD56 and CD11a/CD18 are down-regulated.

TGF-β can induce FOXP3, the master transcription factor of Treg, and regulatory activity in human Vδ2T cells. Scientists observed a strong enhancement of FOXP3 expression and regulatory activity of purified γδ T cells stimulated with phosphoantigen and TGF-β in the presence of vitamin C (Vit C). More importantly, strong hypomethylation of FOXP3 TSDRs was observed only in the presence of Vit C, suggesting that TGF-β frequently expressed in the tumor microenvironment might prime local γδ T cells for suppressive activity if additional epigenetically active signals are present.

TGF-β’s Function in Cancer

In tumors, TGF-β can be either a proto-oncogene or a tumor suppressor, depending on the cell context and tumor stage. TGF-β acts as an antitumor agent in early or primary cancer stages. However, in more advanced cancers, TGF-β favors tumor development.

Most cancers initially express a functional form of TGF-β as well as the proteins involved in the TGF-β signaling pathway. However, during transformation, tumor cells become resistant to the inhibitory effects of TGF-β, thus leading to cell proliferation, invasiveness, and an increase in metastatic potential.

The dual role of TGF-β was shown on a set of experiments with mice skin cancer. The first study demonstrated that TGF-β expression targeted to keratinocytes inhibits benign tumor outgrowth; however, later it enhances malignant progression rate and phenotype of the benign papilloma.

Fig.2 TGF-β canonical signaling pathway. (Tirado-Rodriguez, 2014)

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Reference

1. Tirado-Rodriguez, B.; et al. TGF-β: An Important Mediator of Allergic Disease and a Molecule with Dual Activity in Cancer Development. Journal of Immunology Research. 2014.