Other γδ T Cells Subsets

Because of its non-major histocompatibility complex (MHC) restricted antigen recognition, rapid response to invasive pathogens and early changes of malignant cells, γδ T cells are considered as a member of innate immunity.

Types of Other γδ T Cells Subsets

According to the usage, phenotype, and function of T cell receptors (TCR), human γδ T cells can be divided into several subgroups. Generally speaking, according to the different TCR δ chains, human γδ T cells can be divided into four categories: Vδ1, Vδ2, Vδ3, and Vδ5 γδ T cells. They have different distributions and functions.

Human Vδ3 T cells are the main component of non-Vδ1 and non-Vγ9Vδ2 γδ T cells. They mainly exist in the liver and small intestine epithelium and there are few studies on their effect on the tumor process. Furthermore, a small number of Vδ5 subtypes were found. Vδ4, Vδ6, Vδ7, and Vδ8 T cells were detected in peripheral blood (PB) of patients with lymphoma; however, further studies are needed to assess γ chain pairings and how these subsets are activated.

Fig.1 Illustrations of the different γδ T cell populations in mice and human and how γδ T cells are categorized.
(Xu, 2020)

Features of Other γδ T Cells Subsets

Human γδ T cells expressing Vδ3 TCR contain a small lymphocyte subset in the blood but are enriched in the liver and some patients with chronic viral infection and leukemia. Vδ3 T cells paired with Vγ2 or Vγ3 responded to CD1d and expressed the degranulation marker CD107a. Therefore, Vδ3 T cells are glycolipid reactive T cells with obvious antigen specificity, but their functions are similar to those of natural killer T cells. In addition, Vδ5 γδ T cells co-expressing Vγ4 recognize endothelial protein C receptor (EPCR) on cytomegalovirus (CMV)-infected epithelial cells and epithelial tumor cells by TCR.

Related Diseases and Application of Vδ1⁻ Vδ2⁻ T Cells

Vδ3 T cells are rare in the blood, but abundant in liver, leukemia, and some patients with chronic viral infections. By stimulating mitogen with IL-2, Vδ3 T cells can be expanded to recognize CD1d, which can kill CD1d⁺ target cells, release Th1, Th2, Th17, and other cytokines, and induce dendritic cells (DC) to mature into APCs.

EPCR belongs to MHC I/CD1-like protein molecule, which can protect the endothelial barrier from hypoxia and inflammation. The interaction between Vγ4Vδ5 TCR and EPCR can make γδ T cells recognize CMV infected epithelial cells and epithelial tumor cells with up-regulated EPCR expression.

Fig.2 The tumor cell recognition of γδ T cells. (Liu, 2020)

The great potential of γδ T cells in the immunotherapy of tumor, autoimmune disease, pathogen infection has gradually attracted people's attention. Since there is no MHC restriction on the recognition of tumor antigens by γδ T cells, immunotherapy based on γδ T cells can avoid immune escape caused by down regulation of MHC class I molecules, and also can avoid graft-versus-host effect (GVHD) caused by MHC mismatching αβ T cells. Therefore, γδ T cells may become a new kind of allogeneic cell therapy products in the future.

References

1. Xu, W. L., et al. The Aging of γδ T Cells. Cells. 2020, 9(5): 1181.
2. Liu, Y. X., Zhang, C. The Role of Human γδ T Cells in Anti-Tumor Immunity and Their Potential for Cancer Immunotherapy. Cells. 2020, 9(5): 1206.