γδ T Cell Therapy Development for Epstein-Barr Virus Infections

Increasing evidence of a role for resident memory T-cells and non-conventional γδ T-cells in controlling Epstein-Barr virus (EBV) infection suggests nnew research opportunities. Creative Biolabs is driven to provide global researchers with high-quality services for the development of γδ T cell therapy for EBV infections.

Introduction to EBV

EBV, a gamma herpesvirus, is a ubiquitous cause of infection in humans worldwide. Evidence of prior infection is present in adults throughout the world, with over 90% showing a serologic response. While the onset of infection is delayed in areas with greater socioeconomic development, adults are almost uniformly positive. EBV is most commonly transmitted by contact with respiratory secretions, which promotes access and entry into the reticuloendothelial cells of the upper respiratory tree. While the primary target cell of EBV is the B lymphocyte, infection of a wider range of cell types can occur in immunocompromised hosts, particularly in those of epithelial lineage. Pharyngeal infection is followed by the dissemination of viruses throughout the body, with B lymphocytes as the primary target. The immune response to infection mounts steadily, with the expansion of EBV-specific cytolytic T-cell clones eventually recognizing and controlling the primary infection.

Researches of γδ T Cells Response to EBV

There is good evidence from mouse studies that γδ T-cells are involved in protection from herpesviruses such as murine cytomegalovirus. A role for γδ T-cells in cancer is also suggested both by studies in mouse cancer models and in humans by associations observed between intratumoral γδ T-cell frequency and prognosis. Several lines of evidence now show that γδ T-cells also play an important role in controlling EBV infection and transformation.

Fig.1 Innate lymphocytes target different stages of Epstein–Barr virus (EBV) infection. (Munz, 2017)

• γδ T-Cells in Infectious Mononucleosis (IM)

In IM, direct recognition of EBV infected cells increases γδ frequency. Based on a deeper analysis of the transcriptome, both the Vδ1 and Vδ2 subsets are increased in IM. It is reported that an EBV-negative recipient of a cord blood transplant, who acquired EBV 31 days after transplantation, experienced prolonged high-level EBV viremia yet did not develop any clinical manifestations of EBV-associated disease. This patient lacked detectable EBV-specific αβ T-cells by HLA class I tetramer staining and interferon-gamma ELISpot assays but had large expansions of γδ T-cells that reached almost 50% of total T-cells. These cells were mostly Vδ1 T-cells but a smaller number of Vδ2 T-cells were also present. Interestingly, the γδ T-cells were able to degranulate when exposed to an EBV+ve cell line in vitro suggesting direct recognition of EBV+ve cells was possible.

• γδ T-Cells and EBV-Associated Neoplasms

EBV is associated with malignancies arising in different cell backgrounds. Examples include Burkitt Lymphoma (BL), a tumor of B cells that occurs predominantly in Sub Saharan Africa, and nasopharyngeal carcinoma (NPC) an epithelial carcinoma that occurs at high incidence throughout South East Asia. γδ T-cells are altered in patients with these EBV+ve malignancies. It has been reported that patients with NPC both revealed that while the frequency of γδ T-cells in patients is unaltered, their functional capacity is impaired. Following in vitro culture, peripheral blood mononuclear cells (PBMCs) from NPC patients yielded smaller numbers of γδ cells compared to control donors and were unable to kill an NPC cell line. When tested in cytotoxicity assays, γδ T-cells from patients lacked the ability to kill CNE-2, a tumor cell line established from an NPC patient.

• γδ T-Cells in Mouse Models of EBV

Further support for the role of Vγ9Vδ2 T-cells in the control of EBV comes from studies in mice. The growth of CNE2 cells injected subcutaneously into nude mice was slowed following intravenous administration of Vγ9Vδ2 T-cells. Initial in vivo experiments, using immunodeficient Rag2 / γc / mice injected with LCLs, then showed that the adoptive transfer of magnetically enriched Vγ9Vδ2 T-cells could prevent LCL-induced lymphoproliferative disease and eliminated established LCL tumors. Work by another group also suggests that Vγ9Vδ2 T-cells may be able to eliminate LCLs in vivo without requiring activation via bead selection. Spontaneous EBV-driven lymphoproliferations could be induced in the mice by infecting the cord blood with EBV immediately prior to injection. Adoptive transfer of Vγ9Vδ2 T-cells (generated in vitro but without magnetic bead selection) soon after reconstitution prevented lymphoma development.

Services of γδ T Cells and EBV at Creative Biolabs

Novel techniques have enabled a deeper understanding of the targets, function, and evolution of the γδ T cell responses, and the potential contributions of previously neglected unconventional T cell subsets are increasingly coming to light. As an industry-leading CRO company, Creative Biolabs has been studying cellular immunotherapies for years. Our professional scientists provide γδ T cell services including but not limited to:

• γδ T cell receptors services (including γδ TCR repertoires analysis, γδ TCR transcriptome analysis, γδ TCR generation, and γδ TCR-ligand reaction analysis.).
• γδ T cell development services (including γδ T cell isolation, γδ T cell activation and expansion, γδ T cell characterization, γδ T cell production, and γδ T cell cytotoxicity test.).
• γδ T cell engineering services (including CAR engineered γδ T cell development, αβ TCR-engineered γδ T cells development, and drug-resistant engineered γδ T cells development.).

We can offer you efficient, accurate, and cost-effective services. Please feel free to contact us for detailed information.

Reference

1. Munz, C. Epstein-barr virus-specific immune control by innate lymphocytes. Front Immunol. 2017, 8: 1658.