Targets of γδ T Cell Receptors

γδ T cells are a class of T lymphocytes whose receptors are composed of γ and δ chains. They play important roles in bridging innate and adaptive immunity. The γδ T receptors can directly recognize antigen molecules that are expressed on cancer cells and pathogenic cells without the need for antigen processing. Here introduce several targets of γδ T receptors.

Fig.1 The tumor cell recognition of γδ T cells. (Liu, 2020)

Butyrophilin 3A1 (BTN3A1)

BTN3A1, also known as CD277, is one of three isoforms of BTN3A (BTN3A1, BTN3A2, and BTN3A3), with high structural homology to the B7 superfamily of proteins. It is expressed in various immune cells such as T and NK cells and enhances TCR-induced cytokine production and cell proliferation. BTN3A1 has been indicated as an antigen-presenting molecule required for the activation of Vγ9Vδ2 T cells.

MHC and Related Structures

There are two main types of MHC molecules: class I and class II. Class I MHC molecules are present in all nucleated cells and present peptides to cytotoxic T cells. Class II MHC molecules are present on antigen-presenting cells (APCs). The stress-induced MHC class I-related molecules MICA and MICB have been shown to participate in the recognition by human γδ T cells.

Microorganism-Derived Proteins

γδ T cell receptors have been shown to recognize microorganism-derived proteins in a major histocompatibility complex (MHC)-unrestricted manner. For example, Vδ1 T cells can recognize small lipoprotein antigens produced by bacterial pathogens.

Phosphoantigens

Phosphoantigens (pAgs) are small organophosphorus molecules that are present in infected cells or accumulate intracellularly in certain tumor cells. pAgs are ligands of BTN3A1. BTN3A1-presenting pAgs is required for the stimulation of Vγ9Vδ2 cells in the anti-cancer process.

Heat Shock Proteins (HSP)

HSPs are a family of proteins that are secreted by cells in response to exposure to stressful conditions such as cold, UV light, and hyperthermia. HSPs have been shown to play an important role in immune and inflammatory responses. HSPs are thought of as the ligand of γδ T cell receptors. The interaction of HSPs and γδ T cell receptors may contribute to the activation of the immune system.

Apolipoprotein A-I

Apolipoprotein A-I (apo A-I) is a protein that plays an important role in the transportation and metabolism of lipids. It is the main protein component in high-density lipoprotein (HDL). The main role of apo A-I is in the activation of lecithin cholesterol acyltransferase (LCAT) and the removal of free cholesterol from extrahepatic tissues.

Human MutS Homologue 2 (hMSH2)

hMSH2 is a nuclear protein that is involved in the mismatch repair process after DNA replication. hMSH2 has been revealed to ectopically express on a large number of epithelial tumor cells. It is recognized by both TCR γδ and NKG2D and is involved in Vδ2 T cell-mediated cytolysis of tumor cells.

F1-ATPase-related Structures

F1-ATPase is generally expressed on the mitochondrial membrane. It is also expressed on the membrane of target tumor cells. A surface F1-ATPase-related structure expressing on tumor cells is recognized by Vγ9Vδ2 T cells, which induces the cytolytic activity of Vγ9Vδ2 T cells.

Insulin Peptides

Insulin is a hormone that is produced by beta cells of the pancreatic islets. Its main role is to lower levels of glucose (sugar) in the blood. Autoimmunity to insulin is associated with the pathogenesis of human type I diabetes. γδ T cells have been indicated to inhibit spontaneous diabetes development via recognizing a natural antigen, insulin peptide B:9-23.

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Reference

1. Liu, Y.; Zhang, C. The role of human γδ T cells in anti-tumor immunity and their potential for cancer immunotherapy. Cell. 9(5): 1206.