Little “Life” Makes Sense (III) | The Rising Star of Immunotherapy: γδ T Cells
Release Date:
2023-08-16 17:39
Introduction to γδ T Cells
Immune cells, commonly known as white blood cells, include lymphocytes and various phagocytic cells; they are defined as lymphocytes and other cells capable of recognizing antigens and mounting specific immune responses. Based on their development and migration patterns, surface molecular characteristics, and functional properties, lymphocytes can be classified into T lymphocytes, B lymphocytes, and natural killer (NK) cells.
γδ T cells are a subset of T cells that express a unique T cell receptor (TCR) on their surface. The TCR is composed of four polypeptide chains—α, β, γ, and δ—and the TCR on γδ T cells is an heterodimer formed by the γ and δ chains (TCRγδ). The vast majority of T cells are αβ T cells. In healthy adults, γδ T cells account for only 1% to 5% of peripheral blood T cells and are predominantly localized in mucosal and subcutaneous tissues, such as the gastrointestinal tract, respiratory tract, and genitourinary tract, where they constitute a major component of intraepidermal lymphocytes and intraepithelial lymphocytes (IEL) in mucosal tissues. Most γδ T cells are CD4−CD8−, meaning they do not express CD4 or CD8 molecules on their surface; however, a small subset may express either CD4 or CD8, enabling them to participate in immune regulation and immune responses.
γδ T cells are a subset of T cells that mediate innate immune responses; they can both kill cancer cells and tumor-initiating stem cells and recognize tumor-associated antigens. The surface of T cells expresses numerous markers, such as the T cell receptor (TCR) and cluster of differentiation antigens (CD), which allow T cells to be classified into distinct subsets based on these markers.
γδ T cells represent an emerging frontier in tumor immunology; like αβ T cells, they can exert cytotoxic effector functions (ADCC) and produce pro-inflammatory cytokines. The key distinction is that γδ T cells recognize tumor antigens in an MHC-unrestricted manner, endowing them with the characteristics of a universal cell therapy product. The TCRγδ on the surface of γδ T cells does not require binding to MHC molecules or antigen presentation by antigen-presenting cells (APCs); instead, it can directly recognize and bind antigenic molecules. However, the repertoire of TCRγδ receptors is relatively limited and lacks diversity, resulting in a narrower antigen recognition spectrum for γδ T cells. γδ T cells in different tissues express distinct TCRγδ variants and recognize antigens with varying properties, whereas γδ T cells within the same tissue typically express the same TCRγδ variant and recognize antigens of the same type.
Biological Characteristics of γδ T Cells
Cytotoxicity
Cytotoxicity is the primary biological effector function of γδ T cells and the main mechanism by which they exert their antitumor activity. The TCRγδ can recognize isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate, which accumulate within tumor cells, thereby activating γδ T cells.
Activated γδ T cells can kill tumor cells through multiple mechanisms:
1. Induction of tumor cell apoptosis via the Fas-FasL apoptotic ligand pathway and related apoptosis-inducing ligand receptors;
2. They secrete large amounts of cytokines, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-2 (IL-2), which exert effects on tumor cells and their microenvironment. Among these, IFN-γ is the principal cytokine, exhibiting multiple antitumor activities, including direct inhibition of tumor growth, blockade of angiogenesis, and stimulation of macrophages; it is a key cytokine in γδ T cell–mediated antitumor responses.
3. Exert antibody-dependent cell-mediated cytotoxicity (ADCC) through certain membrane surface receptors, such as FcγRs;
4. Killing tumor cells via the perforin-granzyme B pathway;
Functions and Regulatory Mechanisms of Antitumor γδ T Cells
（ Source: Nature Reviews Cancer )
Participates in immune regulation
Another important biological function of γδ T cells is the secretion of various cytokines and chemokines, which contribute to immune regulation. γδ T cells can produce IL-2 and interferon-γ, thereby exerting effects similar to those of Th1 cells and enhancing cell-mediated anti-infectious immunity. They also secrete IL-17, which plays a critical role in initiating inflammatory responses and in regulating the proliferation and recruitment of neutrophils and monocytes. Furthermore, γδ T cells can modulate the expansion of CD8+ T cells by producing Th2-type cytokines such as IL-4 and IL-10; they assist B-cell activation and antibody production, thereby strengthening humoral immunity; and they regulate TNF-α secretion. In addition, γδ T cells can produce keratinocyte growth factor and connective tissue growth factor, which help maintain epithelial integrity, promote fibroblast proliferation, and facilitate wound healing, thus performing crucial functions within the innate immune system.
The pro-tumorigenic functions of γδ T cells are primarily associated with the production of IL-17A. IL-17A exerts multiple effects, including stimulating tumor cell proliferation, inducing angiogenesis, and recruiting pro-inflammatory or immunosuppressive myeloid cells. To ensure that γδ T cells exert anti-tumor rather than pro-tumorigenic effects, untreated γδ T cells are not used directly for therapy; instead, specifically expanded γδ T cells with defined subsets are employed for treatment.
Functions and Regulatory Mechanisms of Pro-Tumor γδ T Cells
Anti-infection
When the mucosa and subcutaneous tissues become infected, γδ T cells can release cytotoxic molecules such as perforin and granzyme B, upregulate Fas/FasL expression, and secrete IFN-γ, thereby recognizing and killing target cells harboring intracellular bacterial or viral infections. IFN-γ further activates macrophages, prompting them to release IL-15, which in turn recruits γδ T cells to the site of infection and enhances local anti-inflammatory responses. In addition, γδ T cells can also secrete IL-17 to recruit neutrophils, thereby exerting antimicrobial functions.
Inducing dendritic cell maturation
γδ T cells induce dendritic cell (DC) maturation through TCR-CD1 and Fas-FasL interactions, and they also promote the expression of CD86 and MHC class I molecules on immature DCs by secreting TNF-α and IFN-γ. Furthermore, γδ T cells can enhance LPS-induced DC maturation.
Antigen presentation
γδ T cells possess antigen-presenting cell (APC) functions and can initiate antigen-specific immune responses. Activated Vδ2 T cells exhibit professional APC functions and characteristics similar to those of dendritic cells. On the one hand, activated Vδ2 T cells express the chemokine receptor CCR7 on their surface, which directs their migration to lymph nodes and upregulates the expression of MHC class I and MHC class II molecules as well as the co-stimulatory molecules CD80 and CD86. On the other hand, activated Vδ2 T cells can efficiently process and present antigens to both CD4+ T cells and CD8+ T cells, while also delivering robust co-stimulatory signals that strongly promote the proliferation and differentiation of naïve αβ T cells.
Applications of γδ T-cell Therapy
Refractory breast cancer
Breast cancer is one of the most common malignancies among women worldwide, and endocrine therapy and targeted therapies often prove ineffective. In mouse models of early, spontaneous breast (MPyMT) and prostate (Tramp) cancers, expansion of tissue-resident innate-like lymphoid cells—including γδ T cells—has been observed. These immune cells exhibit a distinctive phenotype characterized by tumor-cell elimination via cytotoxic granule-mediated release, IL-15–dependent amplification of cellular transformation, and the expression of NK1.1 (a marker typically expressed on natural killer cells), the collagen-binding molecule CD49a, and the adhesion molecule CD103.
Anti-infective diseases
Infections caused by bacteria, viruses, and parasites can all activate γδ T cells, leading to their expansion and recruitment to the site of infection to exert antimicrobial functions. During infection or cellular necrosis, chemical mediators released by damaged cells can also activate γδ T cells, thereby facilitating the timely clearance of injured cells and enabling immune surveillance.
Autoimmune disease
Among the pathogenic factors of autoimmune diseases, deficiency of γδ T cells is considered one of the contributing causes. In systemic lupus erythematosus and inflammatory bowel diseases, studies have shown that during standard therapeutic regimens, γδ T cell secretion decreases while levels of inhibitory cytokines increase, leading to downregulation of immune responses and attenuation of inflammatory damage. Consequently, enhancing γδ T cell activity has been proposed as a novel therapeutic approach for these conditions.
Common Tumors and Treatment of Malignant Tumors
In the context of cancer immunotherapy, γδ T cells have demonstrated promising therapeutic potential. Clinical trials in renal cell carcinoma have shown that γδ T cells possess intrinsic anti–renal cell carcinoma immunity; an increase in γδ T cell counts is associated with improved overall survival (OS) in patients with advanced disease, and elevated peripheral blood γδ T cell ratios have been validated as robust prognostic markers in advanced renal cell carcinoma. Moreover, γδ T cells are capable of directly killing a broad spectrum of tumor target cells while secreting cytokines and exerting cytotoxic activity to inhibit tumor growth, thereby enhancing patient survival.
Future Prospects for γδ T-Cell Therapy
To date, no serious adverse reactions associated with γδ T-cell therapy have been reported. This therapeutic approach has demonstrated robust efficacy in both hematologic malignancies and solid tumors, independent of specific MHC expression. By sensing stress signals uniquely expressed by cancer cells while sparing healthy cells, γδ T-cell therapy exhibits minimal toxicity and virtually no side effects, thereby holding great promise for broader clinical applications.
The use of clinically established, highly efficient, and safe in vitro expansion methods to generate standard γδ T cells has become an essential step in the treatment of malignant tumors; consequently, the development of an effective and safe in vitro γδ T-cell expansion system represents a pressing challenge that urgently needs to be addressed.
Provided by Hycells Biotechnology
γδ T Cell Samples & Expansion Kit
Hycells Bio offers γδ T-cell donor pre-screening services, in conjunction with the company’s proprietary HiXpan product. TM The γδT cell expansion kit is used to activate and proliferate γδT cells.
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