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γδ T Cell Receptors

γδ T Cell Receptors

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γδ T Cell Overview

Mammalian T lymphocytes, developed from the thymus, play a key important role in immune response and host defense. T lymphocytes recognizing a broad variety of foreign pathogens and tumor antigens, inducing various effector activities base on the T cell receptors (TCRs) on the cell surface. Those T lymphocytes expressing αβ TCRs are commonly known as αβ T cells and those carrying γδ-TCRs are γδ T cells. Despite arising from the same precursor thymocyte, γδ T cells display different TCR repertoires and functional mechanisms from those of αβ T cells.

The human γδ T cells represent a minor category of T lymphocytes, only accounting for <5% of the total T cells, which play an important function in both innate and adaptive immune responses. Published preclinical studies and clinical trials have point out that those minor unconventional γδ T cells, particularly receptor-engineered γδ T cells, exhibiting great potential in the adoptive cellular immunotherapy for multiple tumors and cancers.

Antitumour γδ T cell functions and their regulation Fig.1 Antitumour γδ T cell functions and their regulation. (Silva-Santos, 2019)

Critical γδ T Cell Receptors

By recognizing and binding to a wide variety of antigens or ligands, receptors on the surface of human γδ T cells induce signaling, mediating activation, and diverse effector functions. In addition to featured specific γδ-TCRs, γδ T cells express a variety of important receptors, including natural killer (NK) receptors, Fc receptors, and other co-stimulatory receptors, all of which endow γδ T cells significant effects in pathogen clearance, anti-infection, tumor immune surveillance and killing, etc.

The most featured and important receptor of γδ T cell consisting of γ chain and δ chain. The recombination of γ/δ chain encoded multiple gene segments determines the basis of γδ-TCR diversity. Importantly, the peripheral γδ TCR repertoire is closely related to some pathogenetic pathways.
Human γδ T cells express several important NKRs, which are the characterized receptors on the surface of natural killer (NK) cells. These activating NKRs endow γδ T cell NK cell-like functions, such as cell apoptosis effect by releasing cytolytic granules, engaging in the anti-tumor immune response.
FcγR III is a specific receptor for binding to the Fc region of the IgG antibodies, which is mainly expressed by antibody-mediated effect cells, such as NK cells and macrophages. Activated γδ T cells express FcγR III to induce antibody-dependent cell-mediated cytotoxicity, playing an important role in anti-infection and anti-tumor effects.
Chemokine receptors are cytokine receptors responsible for the binding to various secreted chemokines. These chemokines and corresponding receptors are extensively involved in the development, differentiation, and function of T lymphocyte. It has been reported that γδ T cells, mainly interleukin-17 producing γδ T cells (γδT17 cells), express several chemokine receptors involving inflammatory reaction.
Toll-like receptors are critical receptors in the innate immune system, as well as a bridge connecting non-specific immunity and specific immunity. Studies have identified that γδ T cells expressing toll-like receptors played an important role in early immune responses. And toll-like receptor-ligands reaction enhanced cytotoxicity of γδ T cells on tumor cells.
In addition to the listed critical receptors, γδ T cells also express other effector and regulatory receptors, such as killer inhibitory receptors, tumor necrosis factor receptor, B- and T-lymphocyte attenuator, CD253, etc.

Reference

  1. Silva-Santos, B., et al. γδ T cells: pleiotropic immune effectors with therapeutic potential in cancer. Nature Reviews Cancer. 2019, 19(7): 392-404.
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