Gammadelta T cells

Gamma-delta T cells (γδ T cells) are a subgroup of T lymphocytes that express a T cell receptor consisting of gamma and delta subunits instead of the classic T cell receptor consisting of alpha and beta subunits.

Gamma-delta T cells make up around 0.5-10% of human peripheral blood lymphocytes and, in contrast to the recirculating (lymphocyte recirculation) classical T lymphocytes, are tissue-specific. They are mainly found in the skin, intestine and lung epithelium (lung) (Jee MH et al. 2020; Komano H et al.1995).

In atopic dermatitis, a T cell-mediated disease, both CD4+ and CD8+ T cells are involved. In addition, γδ T cells appear to play an important role in the immune response to contact allergens, although it is still controversial whether γδ T cells have a pro- or anti-inflammatory effect. A special subset of γδ T cells, the dendritic epidermal T cells (DETC), is found in the epidermis of mice and plays an important role in immune surveillance of the skin. DETC are essential for the perception of the environment stressed by contact allergens. Allergen-induced stress proteins expressed on the KC are consequently recognized by the NKG2D receptor on the DETC (Mraz V et al. 2020).

Gamma delta T cells further differ in terms of the antigens they recognize - while the classical α-β T cell receptor recognizes peptide antigens in the context of MHC (major histocompatibility complex) molecules, the gamma delta T cell receptor can also bind directly to intact proteins. γδT cells can recognize a variety of antigens, such as lipids, phosphoantigens and peptides, in an MHC-dependent and -independent manner, suggesting that these cells may also exert antitumor effects against tumors with low mutational load and downregulated MHC. However, signaling from the gamma-delta T cell receptor proceeds in the same way as signaling from the classical T cell receptor via the CD3 complex. The target cells are lysed (Deng J et al. 2022).

The exact function of gamma-delta T cells(γδ T cells) is nevertheless unclear. Since gamma-delta T cells can potentially also recognize endogenous stress proteins, it has been hypothesized that they represent a developmentally early part of the immune system. Thus, gamma delta T cells could detect tissue injuries (caused by infections, UV radiation, inflammation) via the stress proteins and prevent their spread by lysing the affected cells. Among other things, gamma-delta T cell receptors with a specificity for mycobacterial antigens (detected with the aid of purified protein derivative, PPD) could also be detected. Furthermore, gamma-delta T cells have also been associated with autoimmune diseases such as systemic lupus erythematosus, multiple sclerosis, rheumatism and spontaneous abortions. Gamma-delta T cells (γδ T cells) also play an important role in COVID infection. As part of the innate immune system, gamma delta T cells react to inflammation and stressed or infected cells. The gamma delta T cell subset appears to be particularly affected by lymphopenia in COVID-19 patients and often shows activation and exhaustion markers. Especially in children, this subgroup of T cells seems to be the most affected. This is relevant because γδ T cells are more pronounced and more active in early life. γδ T cells can take up, process and present antigens from microbes and human cells. For example, tumor-associated antigens are presented by MHC on γδ T cells to classical T cells (von Massow G et al. 2021).

γδ-T cells are already used for medical purposes in oncology and have potential in cancer therapy (Deng J et al. 2022). In cancer immunotherapy, αβT cells played a fundamental role for a while. However, their dependence on the major histocompatibility complex (MHC), their ability to recognize only mutant peptides, and their low affinity to tumor sites, especially in solid tumors, have hampered their progression into clinical practice. Currently, interest in cancer immunotherapy is focused on γδT cells - cells that act as a bridge between innate and adaptive immunity. It has been shown that γδT cells induce antitumor effects in cancer cells, but not in normal cells. Furthermore, their genetic structure allows easy manipulation for therapeutic intervention.

1. Deng J et al. (2022) Gamma delta (γδ) T cells in cancer immunotherapy; where it comes from, where it will go? Eur J Pharmacol 919:174803.
2. Jee MH et al. (2020) γδ T cells and inflammatory skin diseases. Immunol Rev 298:61-73.
3. Komano H et al.(1995) Homeostatic regulation of intestinal epithelia by intraepithelial gamma delta T cells. Proc Natl Acad Sci USA 92: 6147-51.
4. Mraz V et al (2020) Dendritic Epidermal T Cells in Allergic Contact Dermatitis. Front Immunol 11:874.
5. Morandi F et al. (2020) Engineering the Bridge between Innate and Adaptive Immunity for Cancer Immunotherapy: Focus on γδ T and NK Cells. Cells 9:1757.
6. von Massow G et al. (2021) Gamma Delta T Cells and Their Involvement in COVID-19 Virus Infections. Front Immunol 12:741218.