Regulatory γδ T Cells

γδ T cells have the characteristics of innate and adaptive immune cells and participate in a wide range of pro-inflammatory functions. But so far, there is more and more evidence that γδ T cells also have regulatory functions.

Introduction of Regulatory γδ T Cells

In addition to their significant anti-infectious and anti-tumor properties, γδ T cells can inhibit the maturation and/or activation of peripheral immune cells, leading to beneficial or potential pathological results.

On the one hand, γδ T cells can produce a variety of cytokines and chemokines to regulate other immune cells (such as Tregs) and non-immune cells. On the other hand, they can help B cells. It has been found that the Vγ9Vδ2 T cell subsets expressing CXC chemokine receptor 5 (CXCR5) can induce significant production of IgG even in the absence of antigen, and provide help for primordial B cells to produce IgM, IgG, and IgA antibodies, which indicates that γδ T cells are highly effective in providing B-cytokines and play an important regulatory role in humoral immunity.

Fig.1 γδ T cells exhibiting regulatory properties may be generated in vitro by various means. (Wesch, 2014)

Application of Regulatory γδ T Cells in Autoimmune Diseases

In systemic lupus erythematosus (SLE), it is suggested that CD27⁺CD25⁺ Vδ1 T cells have an immunomodulatory effect through intercellular contact, and the expression of Foxp3 is similar to that of CD4⁺Foxp3⁺. In the presence of TGF-β and IL-2, these regulatory γδ T cells can be produced in vitro in the peripheral blood of active SLE patients under the stimulation of anti- T cell receptor (TCR) γδ. This finding provides a theoretical basis and feasibility for γδ Tregs as a potential target for immunotherapy of autoimmune diseases.

In addition, in the experimental autoimmune encephalomyelitis (EAE) model of human central nervous system autoimmune disease multiple sclerosis, γδ T cells regulate central nervous system inflammation and promote disease recovery through Fas/FasL induced brain-derived T cell apoptosis.

Application of Regulatory γδ T Cells in Allergic Diseases

IL-17⁺ γδ T cells, belonging to the Vγ4 subset, have recently been shown to downregulate the central characteristics of allergic reactions in airway inflammation, including Th2 response and pulmonary eosinophilia. After activated, γδ T cells can produce a variety of cytokines and chemokines, which have the unique plasticity of producing Th1, Th2, and Th17 cytokines, which is conducive to the development and regulation of immune response.

Application of Regulatory γδ T Cells in Cancer

γδ T cells play a potential regulatory role in the control of tumor immune response. For example, some studies have shown that tumor infiltrating γδ T cells in breast cancer can promote the formation of an immunosuppressive microenvironment by inhibiting primitive and effector T cells and impairing dendritic cell (DC) maturation and function. What’s more, γδ Treg cells from breast cancer can induce the immune aging of naive and effector T cells and DC, and this immunosuppressive activity is further amplified by the aging cells themselves. In addition, a new subtype of γδ Treg has been found in human colorectal cancer, which promotes the immunosuppressive microenvironment through metabolic mechanisms. Therefore, some of the γδ T cell subsets are immunosuppressive cells and promote tumor progression in specific cancers.

Fig.2 Secretion by activated γδ cells of multiple cytokines and their physiological roles. (Wu, 2014)

With increasing interest in the therapeutic potential of γδ T cells, we must fully understand their role in the circulatory and tumor microenvironment and their interactions with other cell types. According to the above description, γδ T cells with regulatory function play an important role in immunotherapy of some diseases.

References

1. Wesch, D., et al. Human Gamma Delta T Regulatory Cells in Cancer: Fact or Fiction? Frontiers in Immunology. 2014: 598-598.
2. Wu, Y., et al. γδ T Cells and Their Potential for Immunotherapy. International Journal of Biological Sciences. 2014, 10(2): 119-135.