Dichotomous and stable gamma delta T-cell number and function in healthy individuals (original) (raw)
Related papers
Expansion of Gamma Delta T Cells - A Short Review on Bisphosphonate and K562-Based Methods
Journal of Immunological Sciences, 2018
Gamma Delta T cells As the Next Generation of Effector Cells for Immunotherapy Gamma delta (γδ)-T cells are thymus-derived lymphocytes that differ from αβ-T cells in their anatomical distributions and mechanisms of activation and function. They could be found as resident lymphocytes in human tissues or as circulating lymphocytes in peripheral blood 1 (Vantourout & Hayday, 2013). Unlike αβ-T cells that function exclusively in adaptive immunity, γδ-T cells are innatelike immune cells that recognize malignant cells through their repertoire of activating receptors in a MHC-independent manner, which is similar to natural killer cells 2 (Welsh et al., 1997). Growing interest in the use of γδ-T cells as an alternative form of immunotherapy has been fueled partially by the MHC-restriction mechanism that limits αβ-T cell-based cancer immunotherapy to an autologous setting. γδ-T cells recognize antigens independently of MHC molecules and this mode of action avoids GvHD when used in an allogenic setting 3,4 (Deniger et al., 2014; Xiao et al., 2018). Owing to their repertoire of activating receptors, γδ-T cells have been reported to kill a wide variety of cancer cell lines in vitro such as leukemia, melanoma, lymphomas and other carcinomas 5 (Yoshikawa et al., 2014). Drawing inspiration from the growing field of chimeric antigen receptors (CAR), mRNA CAR-engrafted αβ-T and γδ-T cells have been investigated in parallel and were found to exhibit comparable cytolytic activity against melanoma cells. However, γδ-T cells produced less proinflammatory cytokines as compared with αβ-T which make patients infused with γδ-T cells less susceptible to cytokine release syndrome 6 (Harrer et al., 2017). Given the above qualities, γδ T cells may be produced in large quantity as an off-theshelf agent for cancer immunotherapy.
Cancer immunotherapy with γδ T cells: many paths ahead of us
Cellular & Molecular Immunology, 2020
γδ T cells play uniquely important roles in stress surveillance and immunity for infections and carcinogenesis. Human γδ T cells recognize and kill transformed cells independently of human leukocyte antigen (HLA) restriction, which is an essential feature of conventional αβ T cells. Vγ9Vδ2 γδ T cells, which prevail in the peripheral blood of healthy adults, are activated by microbial or endogenous tumor-derived pyrophosphates by a mechanism dependent on butyrophilin molecules. γδ T cells expressing other T cell receptor variable genes, notably Vδ1, are more abundant in mucosal tissue. In addition to the T cell receptor, γδ T cells usually express activating natural killer (NK) receptors, such as NKp30, NKp44, or NKG2D which binds to stress-inducible surface molecules that are absent on healthy cells but are frequently expressed on malignant cells. Therefore, γδ T cells are endowed with at least two independent recognition systems to sense tumor cells and to initiate anticancer effec...
Mesenchymal cells inhibit expansion but not cytotoxicity exerted by gamma-delta T cells
European Journal of Clinical Investigation, 2009
Background Multipotent mesenchymal stromal cells (MSCs) exert a relevant immunosuppressive activity by inhibiting T-and B-lymphocytes, natural killer (NK) cells and dendritic cell expansion. Nevertheless, a possible activity on gamma ⁄ delta T cells has still not been evaluated. Gamma-delta T lymphocytes play an important role in the control of cancer and they have been shown to be implicated in graft-vs.-host disease. Thus, modulation of activation and proliferation of these cells could be relevant for therapeutic purposes.
Expansion of human γδ T cells for adoptive immunotherapy using a bisphosphonate prodrug
Cancer science, 2017
Cancer immunotherapy with human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) has shown promise because of their ability to recognize and kill most types of tumors in a major histocombatibility complex (MHC) -unrestricted fashion that is independent of the number of tumor mutations. In clinical trials, adoptive transfer of Vγ2Vδ2 T cells has been shown to be safe and does not require preconditioning. In this report, we describe a method for preparing highly enriched human Vγ2Vδ2 T cells using the bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA). PTA stimulated the expansion of Vγ2Vδ2 cells to purities up to 99%. These levels were consistently higher than those observed after expansion with zoledronic acid, the most commonly used stimulator for clinical trials. Cell numbers also averaged more than those obtained with zoledronic acid and the expanded Vγ2Vδ2 cells exhibited high cytotoxicity against tumor c...
Human γδ T Cell Subsets and Their Clinical Applications for Cancer Immunotherapy
Cancers
Gamma delta (γδ) T cells are a minor population of T cells that share adaptive and innate immune properties. In contrast to MHC-restricted alpha beta (αβ) T cells, γδ T cells are activated in an MHC-independent manner, making them ideal candidates for developing allogeneic, off-the-shelf cell-based immunotherapies. As the field of cancer immunotherapy progresses rapidly, different subsets of γδ T cells have been explored. In addition, γδ T cells can be engineered using different gene editing technologies that augment their tumor recognition abilities and antitumor functions. In this review, we outline the unique features of different subsets of human γδ T cells and their antitumor properties. We also summarize the past and the ongoing pre-clinical studies and clinical trials utilizing γδ T cell-based cancer immunotherapy.
PLoS ONE, 2011
Gamma delta T cells (GDTc) lyse a variety of hematological and solid tumour cells in vitro and in vivo, and are thus promising candidates for cellular immunotherapy. We have developed a protocol to expand human GDTc in vitro, yielding highly cytotoxic Vgamma9/Vdelta2 CD27/CD45RA double negative effector memory cells. These cells express CD16, CD45RO, CD56, CD95 and NKG2D. Flow cytometric, clonogenic, and chromium release assays confirmed their specific cytotoxicity against Ph + cell lines in vitro. We have generated a fluorescent and bioluminescent Ph + cell line, EM-2eGFPluc, and established a novel xenogeneic leukemia model. Intravenous injection of EM-2eGFPluc into NOD.Cg-Prkdcscid Il2rgtm1Wjl/ SzJ (NSG) mice resulted in significant dose-dependent bone marrow engraftment; lower levels engrafted in blood, lung, liver and spleen. In vitro-expanded human GDTc injected intraperitoneally were found at higher levels in blood and organs compared to those injected intravenously; GDTc survived at least 33 days post-injection. In therapy experiments, we documented decreased bone marrow leukemia burden in mice treated with GDTc. Live GDTc were found in spleen and bone marrow at endpoint, suggesting the potential usefulness of this therapy.