Exploring the Dynamic Role of Gamma-Delta T Cells in Clinical Pathology: A Systematic Review of Current Knowledge and Future Perspectives

  • Micah Nyabiba Asamba Kenyatta University
  • Miriam Wepukhulu Tharaka University
  • Momo G. Stevens Kenyatta University
Keywords: Gamma-Delta T Cells, Multiple Sclerosis, Immunoregulation, Pathogenesis, Immunotherapy, Malignant Cells, Major Histocompatibility Complex
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Gamma-delta [γδ] T cells are a significant subset of T cells with ability to recognize many antigens without the guidance of major histocompatibility complex (MHC) molecules. A lot of studies have been conducted on them ever since they were discovered 36 years ago. Advances have been made about their structure and function. Thus, there is a need for an up-to-date review about their significance as well as their roles in Multiple Sclerosis. The study aimed to provide an up-to-date knowledge concerning gamma delta T cells in pathogenesis of Multiple Sclerosis (MS). A systematic review methodology was used to scope information from recent studies about gamma delta T cells. The review was carried out in PubMed database and it followed the PRISMA guidelines. The computerized review yielded 60 peer-reviewed articles published between 2011 and 2020. The results showed that gamma delta cells play a critical role in protection against infections and the fight against malignant cells. Most of the reviewed studies highlighted recent advances in research. It was noted that the subset of T cells plays a role in pathogenesis of MS. Several studies have highlighted the protective and detrimental effects of γδ T cells. On the one hand, the cells contribute to the pathogenesis of MS, while, on the other hand, they also help in immunoregulation. However, there is a dearth of literature on their specific role and their mechanism of action. Therefore, further studies are needed about γδ T cells in both human and animal model studies. Based on the findings of the reviewed studies, there is great promise in the use of γδ T cells for MS immunotherapy


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Lawand M, Déchanet-Merville J, Dieu-Nosjean M-C. Key Features of Gamma-Delta T-Cell Subsets in Human Diseases and Their Immunotherapeutic Implications. Frontiers in Immunology [Internet]. 2017 Jun 30 [cited 2020 Jan 17];8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491929/

Vantourout P, Hayday A. Six-of-the-best: unique contributions of γδ T cells to immunology. Nature Reviews Immunology [Internet]. 2013 Jan 25 [cited 2020 Jan 11];13(2):88–100. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951794/

Siegers GM, Lamb LS. Cytotoxic and Regulatory Properties of Circulating Vδ1+ γδ T Cells: A New Player on the Cell Therapy Field? Molecular Therapy [Internet]. 2014 Aug [cited 2020 Jan 12];22(8):1416–22. Available from: https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(16)30738-9

Cordova A, Toia F, La Mendola C, Orlando V, Meraviglia S, Rinaldi G, et al. Characterization of Human γδ T Lymphocytes Infiltrating Primary Malignant Melanomas. Slominski AT, editor. PLoS ONE [Internet]. 2012 Nov 26 [cited 2020 Jan 18];7(11):e49878. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506540/

Thomas ML, Badwe RA, Deshpande RK, Samant UC, Chiplunkar SV. Role of adhesion molecules in recruitment of Vδ1 T cells from the peripheral blood to the tumour tissue of esophageal cancer patients. Cancer Immunology, Immunotherapy [Internet]. 2001 Jun 1 [cited 2021 Sep 30];50(4):218–25. Available from: https://link.springer.com/article/10.1007%2Fs002620100190

Gertner-Dardenne J, Fauriat C, Orlanducci F, Thibult M-L, Pastor S, Fitzgibbon J, et al. The co-receptor BTLA negatively regulates human Vγ9Vδ2 T-cell proliferation: a potential way of immune escape for lymphoma cells. Blood. 2013 Aug 8;122(6):922–31.

Gertner-Dardenne J, Castellano R, Mamessier E, Garbit S, Kochbati E, Etienne A, et al. Human Vγ9Vδ2 T Cells Specifically Recognize and Kill Acute Myeloid Leukemic Blasts. The Journal of Immunology [Internet]. 2012 May 1 [cited 2021 Sep 30];188(9):4701–8. Available from: https://www.jimmunol.org/content/188/9/4701

Ribeiro SãT, Ribot JC, Silva-Santos B. Five Layers of Receptor Signaling in Î3δ T-Cell Differentiation and Activation. Frontiers in Immunology. 2015 Jan 26;6.

Lança T, Costa MF, Gonçalves-Sousa N, Rei M, Grosso AR, Penido C, et al. Protective Role of the Inflammatory CCR2/CCL2 Chemokine Pathway through Recruitment of Type 1 Cytotoxic γδ T Lymphocytes to Tumor Beds. The Journal of Immunology [Internet]. 2013 Jun 15 [cited 2021 Sep 30];190(12):6673–80. Available from: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?db=pubmed&cmd=prlinks&retmode=ref&id=23686489

Muto M, Baghdadi M, Maekawa R, Wada H, Seino K. Myeloid molecular characteristics of human γδ T cells support their acquisition of tumour antigen-presenting capacity. Cancer Immunology, Immunotherapy [Internet]. 2015 Aug 1 [cited 2021 Sep 30];64(8):941–9. Available from: https://link.springer.com/article/10.1007%2Fs00262-015-1700-x

Wu P, Wu D, Ni C, Ye J, Chen W, Hu G, et al. γδT17 Cells Promote the Accumulation and Expansion of Myeloid-Derived Suppressor Cells in Human Colorectal Cancer. Immunity. 2014 May;40(5):785–800.

Ness-Schwickerath KJ, Jin C, Morita CT. Cytokine Requirements for the Differentiation and Expansion of IL-17A– and IL-22–Producing Human Vγ2Vδ2 T Cells. The Journal of Immunology [Internet]. 2010 Jun 15 [cited 2021 Sep 30];184(12):7268–80. Available from: https://www.jimmunol.org/content/184/12/7268

Michel M-L ., Pang DJ, Haque SFY, Potocnik AJ, Pennington DJ, Hayday AC. Interleukin 7 (IL-7) selectively promotes mouse and human IL-17-producing cells. Proceedings of the National Academy of Sciences [Internet]. 2012 Oct 9 [cited 2020 Nov 10];109(43):17549–54. Available from: https://www.pnas.org/content/pnas/109/43/17549.full.pdf

Ribot JC, Ribeiro ST, Correia DV, Sousa AE, Silva-Santos B. Human γδ Thymocytes Are Functionally Immature and Differentiate into Cytotoxic Type 1 Effector T Cells upon IL-2/IL-15 Signaling. The Journal of Immunology [Internet]. 2014 Mar 1 [cited 2021 Sep 30];192(5):2237–43. Available from: https://www.jimmunol.org/content/192/5/2237

Silva-Santos B, Serre K, Norell H. γδ T cells in cancer. Nature Reviews Immunology [Internet]. 2015 Oct 9 [cited 2020 Jan 11];15(11):683–91. Available from: https://www.nature.com/articles/nri3904

Couzi L, Pitard V, Sicard X, Garrigue I, Hawchar O, Merville P, et al. Antibody-dependent anti-cytomegalovirus activity of human γδ T cells expressing CD16 (FcγRIIIa). Blood. 2012 Feb 9;119(6):1418–27.

Kabelitz D. Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran. Cells. 2020 Nov 30;9(12):2564.

Rigau M, Ostrouska S, Fulford TS, Johnson DN, Woods K, Ruan Z, et al. Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells. Science. 2020 Jan 9;367(6478):eaay5516.

Fonseca S, Pereira V, Lau C, Teixeira M dos A, Bini-Antunes M, Lima M. Human Peripheral Blood Gamma Delta T Cells: Report on a Series of Healthy Caucasian Portuguese Adults and Comprehensive Review of the Literature. Cells. 2020 Mar 16;9(3):729.

Kabelitz D, Serrano R, Kouakanou L, Peters C, Kalyan S. Cancer immunotherapy with γδ T cells: many paths ahead of us. Cellular & Molecular Immunology. 2020 Jul 22;17(9):925–39.

Xu W, Lau ZWX, Fulop T, Larbi A. The Aging of γδ T Cells. Cells. 2020 May 9;9(5):1181.

Herrmann T, Fichtner AS, Karunakaran MM. An Update on the Molecular Basis of Phosphoantigen Recognition by Vγ9Vδ2 T Cells. Cells. 2020 Jun 9;9(6):1433.

Serrano R, Wesch D, Kabelitz D. Activation of Human γδ T Cells: Modulation by Toll-Like Receptor 8 Ligands and Role of Monocytes. Cells. 2020 Mar 13;9(3):713.

Nussbaumer O, Thurnher M. Functional Phenotypes of Human Vγ9Vδ2 T Cells in Lymphoid Stress Surveillance. Cells. 2020 Mar 22;9(3):772.

Tosolini M, Pont F, Poupot M, Vergez F, Nicolau-Travers M-L, Vermijlen D, et al. Assessment of tumour-infiltrating TCRVγ9Vδ2γδlymphocyte abundance by deconvolution of human cancers microarrays. OncoImmunology. 2017 Feb 6;6(3):e1284723.

Wesch D, Kabelitz D, Oberg H. Tumor resistance mechanisms and their consequences on γδ T cell activation. Immunological Reviews. 2020 Oct 13;298(1):84–98.

Jonescheit H, Oberg H-H, Gonnermann D, Hermes M, Sulaj V, Peters C, et al. Influence of Indoleamine-2,3-Dioxygenase and Its Metabolite Kynurenine on γδ T Cell Cytotoxicity against Ductal Pancreatic Adenocarcinoma Cells. Cells. 2020 May 6;9(5):1140.

Kouakanou L, Xu Y, Peters C, He J, Wu Y, Yin Z, et al. Vitamin C promotes the proliferation and effector functions of human γδ T cells. Cellular & Molecular Immunology. 2019 Jun 6;17(5):462–73.

Yazdanifar M, Barbarito G, Bertaina A, Airoldi I. γδ T Cells: The Ideal Tool for Cancer Immunotherapy. Cells. 2020 May 24;9(5):1305.

Xu Y, Xiang Z, Alnaggar M, Kouakanou L, Li J, He J, et al. Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer. Cellular & Molecular Immunology. 2020 Sep 16;18(2):427–39.

Pawlik-Gwozdecka D, Zieliński M, Sakowska J, Adamkiewicz-Drożyńska E, Trzonkowski P, Niedźwiecki M. CD8+ gamma-delta T cells correlate with favorable prognostic factors in childhood acute lymphoblastic leukaemia. Archives of Medical Science. 2021 Mar 1;17(2):561–3.

Arruda LCM, Gaballa A, Uhlin M. Impact of γδ T cells on clinical outcome of hematopoietic stem cell transplantation: systematic review and meta-analysis. Blood Advances. 2019 Nov 12;3(21):3436–48.

Harly C, Guillaume Y, Nedellec S, Peigné C-M, Mönkkönen H, Mönkkönen J, et al. Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset. Blood [Internet]. 2012 Sep 13 [cited 2020 Jan 14];120(11):2269–79. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679641/

Karunakaran MM, Willcox CR, Salim M, Paletta D, Fichtner AS, Noll A, et al. Butyrophilin-2A1 Directly Binds Germline-Encoded Regions of the Vγ9Vδ2 TCR and Is Essential for Phosphoantigen Sensing. Immunity. 2020 Mar;52(3):487-498.e6.

Melandri D, Zlatareva I, Chaleil RAG, Dart RJ, Chancellor A, Nussbaumer O, et al. The γδTCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness. Nature Immunology [Internet]. 2018 Nov 12 [cited 2021 Sep 30];19(12):1352–65. Available from: https://dx.doi.org/10.1038%2Fs41590-018-0253-5

Fichtner AS, Ravens S, Prinz I. Human γδ TCR Repertoires in Health and Disease. Cells [Internet]. 2020 Mar 26 [cited 2021 Sep 30];9(4):800. Available from: https://dx.doi.org/10.3390%2Fcells9040800

Rampoldi F, Ullrich L, Prinz I. Revisiting the Interaction of γδ T-Cells and B-Cells. Cells [Internet]. 2020 Mar 18 [cited 2021 Sep 30];9(3):743. Available from: https://dx.doi.org/10.3390%2Fcells9030743

Witherden DA, Watanabe M, Garijo O, Rieder SE, Sarkisyan G, Cronin SJF, et al. The CD100 receptor interacts with its plexin B2 ligand to regulate epidermal γδ T cell function. Immunity [Internet]. 2012 Aug 24 [cited 2021 Sep 30];37(2):314–25. Available from: https://www.ncbi.nlm.nih.gov/pubmed/22902232

Johnson MD, Witherden DA, Havran WL. The Role of Tissue-resident γδ T Cells in Stress Surveillance and Tissue Maintenance. Cells. 2020 Mar 11;9(3):686.

Bank I. The Role of Gamma Delta T Cells in Autoimmune Rheumatic Diseases. Cells. 2020 Feb 18;9(2):462.

Clohosey ML, Mann BT, Ryan PL, Apanasovich TV, Maggirwar SB, Pennington DJ, et al. Comparable Vδ2 Cell Functional Characteristics in Virally Suppressed People Living with HIV and Uninfected Individuals. Cells [Internet]. 2020 Dec 1 [cited 2021 Sep 30];9(12):E2568. Available from: https://www.ncbi.nlm.nih.gov/pubmed/33271808

Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nature Medicine. 2015 Jul 20;21(8):938–45.

Yoo S-Y, Park HE, Kim JH, Wen X, Jeong S, Cho N-Y, et al. Whole-Slide Image Analysis Reveals Quantitative Landscape of Tumor–Immune Microenvironment in Colorectal Cancers. Clinical Cancer Research [Internet]. 2019 Nov 22 [cited 2021 Sep 30];26(4):870–81. Available from: https://dx.doi.org/10.1158%2F1078-0432.CCR-19-1159

Chabab G, Boissière-Michot F, Mollevi C, Ramos J, Lopez-Crapez E, Colombo P-E, et al. Diversity of Tumor-Infiltrating, γδ T-Cell Abundance in Solid Cancers. Cells [Internet]. 2020 Jun 24 [cited 2021 Sep 30];9(6):1537. Available from: https://dx.doi.org/10.3390%2Fcells9061537

Wang Y, Jia A, Bi Y, Wang Y, Yang Q, Cao Y, et al. Targeting Myeloid-Derived Suppressor Cells in Cancer Immunotherapy. Cancers. 2020 Sep 15;12(9):2626.

Künkele K-P, Wesch D, Oberg H-H, Aichinger M, Supper V, Baumann C. Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy? Cells [Internet]. 2020 Mar 30 [cited 2021 Sep 30];9(4):829. Available from: https://dx.doi.org/10.3390%2Fcells9040829

Liu Y, Zhang C. The Role of Human γδ T Cells in Anti-Tumor Immunity and Their Potential for Cancer Immunotherapy. Cells. 2020 May 13;9(5):1206.

Zúñiga LA, Shen W-J, Joyce-Shaikh B, Pyatnova EA, Richards AG, Thom C, et al. IL-17 Regulates Adipogenesis, Glucose Homeostasis, and Obesity. The Journal of Immunology. 2010 Oct 29;185(11):6947–59.

Hu B, Jin C, Zeng X, Resch JM, Jedrychowski MP, Yang Z, et al. γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis. Nature [Internet]. 2020 Feb 1 [cited 2020 Nov 23];578(7796):610–4. Available from: https://www.nature.com/articles/s41586-020-2028-z#Sec2

Acuto O, Hussey RE, Fitzgerald KA, Protentis JP, Meuer SC, Schlossman SF, et al. The human T cell receptor: Appearance in ontogeny and biochemical relationship of α and β subunits on IL-2 dependent clones and T cell tumours. Cell. 1983 Oct;34(3):717–26.

Vermijlen D, Gatti D, Kouzeli A, Rus T, Eberl M. γδ T cell responses: How many ligands will it take till we know? Seminars in Cell & Developmental Biology. 2018 Dec;84:75–86.

Adams EJ, Gu S, Luoma AM. Human gamma delta T cells: Evolution and ligand recognition. Cellular Immunology [Internet]. 2015 Jul [cited 2020 Jan 17];296(1):31–40. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466157/

Hayday AC. γδ T Cell Update: Adaptate Orchestrators of Immune Surveillance. The Journal of Immunology. 2019 Jul 8;203(2):311–20.

Li X, Kang N, Zhang X, Dong X, Wei W, Cui L, et al. Generation of Human Regulatory γδ T Cells by TCRγδ Stimulation in the Presence of TGF-β and Their Involvement in the Pathogenesis of Systemic Lupus Erythematosus. The Journal of Immunology. 2011 May 11;186(12):6693–700.

Huang D, Chen CY, Zhang M, Qiu L, Shen Y, Du G, et al. Clonal immune responses of Mycobacterium-specific γδ T cells in tuberculous and non-tuberculous tissues during M. tuberculosis infection. PloS One [Internet]. 2012 [cited 2021 Oct 2];7(2):e30631. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=22319574

Kabelitz D. Editorial: “Recent advances in gamma/delta T cell biology: new ligands, new functions, and new translational perspectives.” Frontiers in Immunology. 2015;6.

Bekiaris V, Å edý JR, Ware CF. Mixing Signals: Molecular Turn Ons and Turn Offs for Innate Î3δ T-Cells. Frontiers in Immunology. 2014 Dec 18;5.

Rajoriya N, Fergusson JR, Leithead JA, Klenerman P. Gamma Delta T-lymphocytes in Hepatitis C and Chronic Liver Disease. Frontiers in Immunology. 2014 Aug 26;5.

Su D, Shen M, Li X, Sun L. Roles of T Cells in the Pathogenesis of Autoimmune Diseases. Clinical and Developmental Immunology. 2013;2013:1–6.

Edwards SC, Sutton CE, Ladell K, Grant EJ, McLaren JE, Roche F, et al. A population of proinflammatory T cells coexpresses αβ and γδ T cell receptors in mice and humans. Journal of Experimental Medicine. 2020 Feb 27;217(5).

21 September, 2023
How to Cite
Asamba, M., Wepukhulu, M., & Stevens, M. (2023). Exploring the Dynamic Role of Gamma-Delta T Cells in Clinical Pathology: A Systematic Review of Current Knowledge and Future Perspectives. East African Journal of Health and Science, 6(1), 402-414. https://doi.org/10.37284/eajhs.6.1.1394