γδ T Cell Subsets Based on Function

γδ T cells have pleiotropy with traditional αβ T cells. Resting γδ T cells are stimulated by different polarizing factors and can be induced into various functional subgroups in vitro to produce different functions.

Background

About 5% of peripheral blood T cells were found in the peripheral blood, but more abundant in mucosal tissue. Based on the recognized ligands and their general lack of major histocompatibility complex (MHC) restriction, γδ T cells are considered as unconventional T cells connecting innate immunity and adaptive immunity. According to their functions, γδ T cells can be divided into two types: effector γδ T cells and regulatory γδ T cells. γδ T cells produce a variety of cytokines and play a cytotoxic effect. They can be used as antigen presenting cells and have regulatory activity. As a result, γδ T cells have incredible therapeutic potential in diseases such as autoimmune diseases, pathogen infection, and cancer. A more comprehensive understanding of these processes will allow us to manipulate the plasticity of γδ T cells to ensure optimal efficacy and ultimately improve patient outcomes.

Fig.1 Effector and regulatory functions of γδ T cells in the tumor microenvironment. (Paul, 2016)

• Effector γδ T Cells

γδ T cells can produce different kinds of cytokines and chemokines, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and growth factors such as IGF-1. When activated by stimulants, these cells act by secreting cytokines, through antibody dependent cytotoxicity (ADCC) and other processes, known as effector γδ T cells. The effector function of γδ T cells in tumor microenvironment is induced by the interaction between γδ TCR and stress-induced molecules expressed on tumor cells.

• Regulatory γδ T Cells

Regulatory γδ T (γδ Treg) cell also known as γδ suppressor T cells. They can regulate the immune response by interacting with other cells, such as helping B cells and providing antigens for αβ T cells. Other important functions include macrophage recruitment and cytolytic activity. γδ Treg cells can induce immune aging by targeting T cells and dendritic cells (DC). γδ T17 cells are another subgroup of proinflammatory regulatory T cells, which are determined by their production of interleukin-17 (IL-17). In various types of tumors, γδ T17 cells promote the accumulation and expansion of immunosuppressive cells and accelerate the development of tumors.

Fig.2 Polarization and responses of human γδ T cell subsets to tumors. (Wu, 2017)

Application of γδ T Cells

These functions of γδ T cell subsets play important roles in the regulation of innate immune resistance to a variety of infections, showing strong and extensive cytotoxic activity to human tumor cells. Due to the simultaneous expression of natural killer receptors, such as NKG2D (natural-killer group 2, member D) and γδ T cell receptors, they are considered to be the link between innate immunity and adaptive immunity. In addition, activated γδ T cells expressed high levels of antigen-presenting cell-related molecules and could present peptide antigens from damaged cells to αβ T cells. Based on these antimicrobial and antitumor properties of γδ T cells, some preclinical and clinical trials have been carried out to develop therapeutic methods against infections and malignant tumors.

References

1. Paul, S., Lal, G. Regulatory and effector functions of gamma-delta (γδ) T cells and their therapeutic potential in adoptive cellular therapy for cancer. International Journal of Cancer. 2016, 139(5): 976-985.
2. Wu, D., et al. Human γδ T-cell subsets and their involvement in tumor immunity. Cellular & Molecular Immunology. 2017, 14(3): 245-253.