γδ T Cell Therapy Development for Cytomegalovirus Infections

Due to the toxicities of antiviral drugs, there is a growing interest in evaluating γδ T cell-mediated immunity to improve the diagnosis and management of cytomegalovirus (CMV) infection. Studies of γδ T cells open the door to novel cellular immunotherapies. As an advanced bio-pharmaceutical CRO company, Creative Biolabs is driven to provide a series of γδ T cells development and engineering services to promote your project success.

Introduction to Cytomegalovirus (CMV)

Human cytomegalovirus (HCMV) elicits a very broad spectrum of immune responses starting with innate mechanisms, including, inflammatory cytokines from virus-cell binding, natural killer cell induction which subsequently drives adaptive immunity, including antibody production and the generation of CD4⁺ and CD8⁺ T cell responses. However, the virus is also a paradigm for pathogen mediated immune evasion, expressing multiple genes that interfere with multiple innate and adaptive immune responses. Therefore, it is somewhat of a paradox that HCMV is usually an asymptomatic infection that generates a strong immune response controlling viral replication but, if the immune system is suppressed, this leads to unchecked viral replication and ultimately morbidity and mortality. However, it is also evident that the primary immune response is unable to prevent the virus from establishing latency, and the subsequent long-term immune response is unable to clear the virus, which, consequently, remains with the host for life.

Relationship of γδ T and CMV

Evidence from kidney, lung, and stem cell transplant recipients suggests that a subset of gamma delta (γδ) T cells (the minor V2 negative subpopulation) are expanded following HCMV reactivation in these patients. This CMV-induced γδ T cell expansion did not involve the Vδ2 subset, which is usually the main subset of γδ T cells observed in the peripheral blood. Surprisingly, this increase can concern any of the Vδ1, Vδ3, and Vδ5 sub-populations (collectively designated as Vδ2^neg γδ T cells). This initial observation, since largely confirmed by others, suggested that a population of Vδ2^neg γδ T cells might play an important role in the immune response to CMV infection. Further evidence from some of these studies using in vitro cultured cells showed the ability to mediated cytotoxicity of HCMV infected target cells. The role for γδ T cells in the control of CMV infection is further supported in mouse cytomegalovirus (MCMV) infected mice which show an increase of these cells in the salivary gland. Primary infection shows accumulation in the liver and antibody depletion of gamma delta cells before infection correlates with an increase in MCMV titers.

Fig.1 Phenotypes of long-term CMV-induced NK, CD8⁺ ab, and yd T cells in humans and C57BL/6 mice. (Khairallah, 2017)

Clinical Interest of γδ T Cells Response to CMV

γδ T cells represent an interesting clinical target in the context of CMV infection.

• Detection immune response to CMV

Quantifying Vδ2 γδ T cells in the blood is an easy assay to detect immune response to CMV in patients. It is proven that as reliable as CMV-specific αβ T cell detection, evidencing Vδ2 γδ T cell expansion is more convenient and cheaper (one-step direct staining in whole blood with only anti-CD3, anti-pan-delta, and anti-Vδ2 antibodies) than the detection of CMV-specific αβ T cells using MHC tetramers or activation by viral peptides.

• Antiviral functions

The antiviral functions of γδ T cells supported the development of new graft preparation procedures in stem cell transplantation. In recent clinical trials, depletion of whole T cells from the graft to avoid graft-versus-host disease was replaced by αβ T cell depletion. The goal of such procedure is to keep γδ T cells within the graft to prevent CMV infection and promote graft versus leukemia/lymphoma effect because of the γδ T cell reactivity against tumor cells.

• Development of vaccination

The ongoing identification of stress-induced self-antigens expressed by CMV-infected cells could pave the way toward the development of vaccination strategies using these antigens, in a similar way as what has been done in clinical trials using phosphoantigens activating Vγ9Vδ2 T cells.

• Cell therapy

Development of cell therapy based on γδ T cells activated in vitro and reinjected in patients has been proposed in cancer, and could also prove useful in CMV infection.

Services at Creative Biolabs

The ability of CMV-induced γδ T cells to act independently of other immune cells opens the door to the development of novel cellular immunotherapies that could be particularly beneficial for immunocompromised transplant recipients. As a global-leading CRO company, Creative Biolabs has a team of excellent scientists specialized in cellular immunotherapies. We provide comprehensive services including but not limited to:

• γδ TCR receptors services
• γδ T cell isolation, characterization, and production services
• γδ T Cell Engineering Services
• γδ T cell phenotypic and functional characterization
• γδ T cell cytotoxicity test

Please unhesitatingly contact us for more information.

Reference

1. Khairallah, C.; et al. Gammadelta T cell-mediated immunity to cytomegalovirus infection. Front Immunol. 2017, 8: 105.