γδ T Cell Therapy Development for Parasitic Infections

Short Introduction to γδ T Cells

γδ T cells are unconventional T lymphocytes which are increasingly being appreciated for their unique role in integrating the innate and adaptive arms of the immune system. Comprising approximately 2-5% of peripheral blood T cells in healthy adults, they can uniquely recognize a broad range of antigens without the need for major histocompatibility complex (MHC) and can both establish and regulate the inflammatory response.

Fig.1 γδ T cells modulation using different substances. (Yazdanifar, 2020)

γδ T Cells and Plasmodium

Plasmodium is a genus of unicellular eukaryotes that are obligate parasites of vertebrates and insects. The life cycles of plasmodium species involve development in a blood-feeding insect host which then injects parasites into a vertebrate host during a blood meal. Parasites grow within a vertebrate body tissue (often the liver) before entering the bloodstream to infect red blood cells. The ensuing destruction of host red blood cells can result in a disease, called malaria. During this infection, some parasites are picked up by a blood-feeding insect (mosquitoes in a majority of the cases), continuing the life cycle.

Fig.2 Life cycle of Plasmodium falciparum. (Maier, 2018)

• γδ T Cells and Plasmodium Chabaudi (P. Chabaudi) Infection

Mice deficient in γδ T cells experience higher parasitemia during acute P. chabaudi infection, as well as substantial parasitemic recrudescence. The depletion of γδ T cells during chronic P. chabaudi infection in B cell-deficient mice also resulted in insignificantly worsened parasitemia. γδ T cells expand and become activated in later stages of P. chabaudi malaria much later than CD4+ and CD8+ αβ T cell activation-even when acute stages are cleared early by drug treatment. This clonal expansion of γδ T cell occurred primarily in murine blood, spleen, lung, and liver, and effectively prevented late-stage parasite recurrence.

• γδ T Cells and Plasmodium Berghei (P. Berghei) Infection

B-cell-immunodeficient mice and γδ T-cell-deficient mice were incapable of protecting against P. berghei X-ray analysis test (XAT) parasites. γδ T-cell-deficient mice developed reduced levels of antigen-specific antibodies during the late phase of infection. The numbers of follicular helper T cells and germinal center B cells in γδ T-cell-deficient mice were lower than in wild-type mice during the late phase of infection. Expression profiling of humoral immunity-related cytokines in γδ T cells showed that interleukin-21 (IL-21) and interferon-γ (IFN-γ) were increased during the early stage of infection. Furthermore, blockade of IL-21 and IFN-γ signaling during the early stage of infection led to a reduction in follicular helper T cells and germinal center B cells. γδ T-cell production of IL-21 and IFN-γ is crucial for the development and maintenance of follicular helper T cells and germinal center B cells during the late phase of infection.

In the non-lethal P. berghei XAT model, control of parasitemia seems to be at least partially mediated by CD40 signaling and boosting of dendritic cell activation. Following vaccination with lethal P. berghei ANKA sporozoites, γδ T cells contribute to pre-erythrocytic immunity by recruiting dendritic cells and CD8+ T cells during vaccination but are not required to prevent infection upon blood-stage challenge. Mice depleted of γδ T cells by monoclonal antibody were protected from cerebral malaria (the most severe form of malaria) due to P. berghei, but mice genetically depleted of γδ T cells did not show this effect, implying that effective activation of γδ T cells is extraordinarily time-sensitive.

• γδ T Cells and Plasmodium Yoelii (P. Yoelii) Infection

In mice lacking αβ T cells, γδ T cells substantially influenced immunity to P. yoelii liver stages, but could not rescue immunity to blood stages, suggesting that at least in this parasite strain, γδ T cells act as important effectors and their cytotoxicity may become more effective after interaction with CD4+ T cells. Mice lacking γδ T cells had significantly higher P. yoelii burden in the liver than similarly challenged immunocompetent mice, suggesting a potential role for γδ T cells in the development of pre-erythrocytic immunity. These differences could potentially be explained solely by the different murine parasite strains used, as P. yoelii irradiated sporozoite vaccination does not induce sterile immunity. Murine models have also suggested the role of γδ T cell in disease pathogenesis.

• γδ T Cells and Plasmodium Falciparum (P. falciparum) Infection

γδ T cells specifically and massively expanded upon activation with P. falciparum culture supernatant. These activated cells gain cytolytic potential by upregulating cytotoxic effector proteins and IFN-γ. The killer cells bound to infected red blood cells (RBCs) and killed intracellular P. falciparum via the transfer of the granzymes, which was mediated by granulysin in a stage-specific manner. Several vital plasmodial proteins were efficiently destroyed by granzyme B, suggesting proteolytic degradation of these proteins is essential in the lymphocyte-mediated death pathway. Overall, these data establish a granzyme- and granulysin-mediated innate immune mechanism exerted by γδ T cells to kill late-stage blood-residing P. falciparum.

Fig.3 Model for Vγ9Vδ2 γδ T cell response to P. falciparum. (Dantzler, 2018)

Our Services

Although there are still many unsolved challenges in the treatment and clinical application of γδ T cells. However, with the in-depth study of this kind of T cells, it is not difficult to find that γδ T cells have great advantages and development space in the treatment of diseases. As a leader in the research of γδ T cells, Creative Biolabs provides high-quality γδ T cell development services to promote the treatment of pathogen infections. Our high-quality customized services cover the entire γδ T cell development process, including isolation, activation and expansion, characterization, production, cytotoxicity test, etc. In addition, we provide γδ T cell receptors analysis services, including γδ TCR repertoires analysis and γδ TCR transcriptome analysis.

Please feel free to contact us for a discussion with our scientists.

References

1. Yazdanifar, M.; et al. γδ T cells: the ideal tool for cancer immunotherapy. 2020.
2. Maier, A. G.; et al. Plasmodium falciparum. Trends in Parasitology. 2018.
3. Dantzler, K. W.; Jagannathan, P. γδ T cells in antimalarial immunity: new insights into their diverse functions in protection and tolerance. Frontiers in Immunology. 2018, 9.
4. Deroost, K.; Langhorne, J. Gamma/Delta T cells and their role in protection against malaria. Frontiers in Immunology. 2018, 9.