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Five Layers of Receptor Signaling in γδ T-Cell Differentiation and Activation
Open accessAbstract
The contributions of γδ T-cells to immunity to infection or tumors critically depend on their activation and differentiation into effectors capable of secreting cytokines and killing infected or transformed cells. These processes are molecularly controlled by surface receptors that capture key extracellular cues and convey downstream intracellular signals that regulate γδ T-cell physiology. The understanding of how environmental signals are integrated by γδ T-cells is critical for their manipulation in clinical settings. Here, we discuss how different classes of surface receptors impact on human and murine γδ T-cell differentiation, activation, and expansion. In particular, we review the role of five receptor types: the T-cell receptor (TCR), costimulatory receptors, cytokine receptors, NK receptors, and inhibitory receptors. Some of the key players are the costimulatory receptors CD27 and CD28, which differentially impact on pro-inflammatory subsets of γδ T-cells; the cytokine receptors IL-2R, IL-7R, and IL-15R, which drive functional differentiation and expansion of γδ T-cells; the NK receptor NKG2D and its contribution to γδ T-cell cytotoxicity; and the inhibitory receptors PD-1 and BTLA that control γδ T-cell homeostasis. We discuss these and other receptors in the context of a five-step model of receptor signaling in γδ T-cell differentiation and activation, and discuss its implications for the manipulation of γδ T-cells in immunotherapy.
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“IL-12 and IL-18 promote IFN-γ production, while IL-1β and IL-23 drive them towards IL-17-producing cells (14).”
From Comparing Mouse and Human Tissue-Resident γδ T Cells (2022) · cites this paper as [14]
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“T cells can also be activated via TCR-independent mechanisms 6 including natural killer group 2D (NKG2D), a receptor shared by NK, , and CD8+ T cells that binds to MHC class I polypeptide-related sequence-A and -”
Joalland, N., & Scotet, E. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00992 · Cited by 12
“Importantly, this Self -reactive nature of Vγ9Vδ2 T cells needs to be tightly regulated by a set of various molecules [see (15) and (16), for recent reviews], such as adhesion molecules (i.”
BackgroundGrogan, L. F., Mulvenna, J. P., Gummer, J. P. A., Scheele, B. C., Berger, L., Cashins, S. D., McFadden, M., Harlow, P. S., Hunter, D. A., Trengove, R. D., et al. (2018) · Scientific Data · doi:10.1038/sdata.2018.33 · Cited by 13
Restriction of innate Tγδ17 cell plasticity by an AP-1 regulatory axis
Parker, M. E., Mehta, N. U., Liao, T.-C., Tomaszewski, W. H., Snyder, S., Busch, J., & Ciofani, M. (2025) · Nature Immunology · doi:10.1038/s41590-025-02206-7 · Cited by 12
Ruchti, F., Tuor, M., Mathew, L., McCarthy, N. E., & LeibundGut‐Landmann, S. (2024) · PLoS Pathogens · doi:10.1371/journal.ppat.1011668 · Cited by 9
Barragué, H., Fontaine, J., Abravanel, F., Mauré, E., Péron, J., Alric, L., Dubois, M., Izopet, J., & Champagne, É. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2000187 · Cited by 10
The multisensory regulation of unconventional T cell homeostasis
Darrigues, J., Almeida, V., Conti, E., & Ribot, J. C. (2022) · Seminars in Immunology · doi:10.1016/j.smim.2022.101657 · Cited by 10
Self-citationThe therapeutic role of γδT cells in TNBC
Li, W., Zhao, X., Ren, C., Gao, S., Han, Q., Lu, M. M., & Li, X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1420107 · Cited by 9
“NKG2D, a C-type lectin receptor, binds ligands that are typically absent in most normal tissues but are overexpressed on tumor cells, thereby enabling gd T cells to recognize and eliminate tumor cells (56).”
BackgroundThe Role of Nuclear Factor-κB in Cancer Immunity and Immunoediting
Mukherjee, S., Pati, S., Dhar, S., Sarkar, T., Paul, S., Basak, U., Chakraborty, S., & Sa, G. (2025) · Cancer Control · doi:10.1177/10732748251406677 · Cited by 9
Assy, L., Khalil, S. M., Attia, M., & Salem, M. L. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109402 · Cited by 9
Berillo, O., Comeau, K., Caillon, A., Leclerc, S., Shokoples, B. G., Mahmoud, A., Andelfinger, G., Paradis, P., & Schiffrin, E. L. (2024) · Journal of Hypertension · doi:10.1097/hjh.0000000000003725 · Cited by 9
“Finally, CD28-positive d T-lymphocytes could have a pathogenic role in human hypertension associated with obesity, and could be a potential target for therapy.”
BackgroundPean, P., Nouhin, J., Meng, R., Madec, Y., Borand, L., Marcy, O., Laureillard, D., Fernandez, M., Barré‐Sinoussi, F., Weiss, L., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02018 · Cited by 9
γ9δ2 T-Cell Expansion and Phenotypic Profile Are Reflected in the CDR3δ Repertoire of Healthy Adults
Vyborova, A., Janssen, A., Gatti, L. C. D. E., Karaiskaki, F., Yonika, A., van Dooremalen, S., Sanders, J., Beringer, D. X., Straetemans, T., Sebestyén, Z., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.915366 · Cited by 8
“org 8 generally considered “signal one” (44), on the landscape of the remaining NKRs and thus on the net NKR signal.”
BackgroundAngiotensin II-Induced Memory γδ T Cells Sensitize Mice to a Mild Hypertensive Stimulus
Comeau, K., Shokoples, B. G., Caillon, A., Paradis, P., & Schiffrin, E. L. (2023) · American Journal of Hypertension · doi:10.1093/ajh/hpad072 · Cited by 9
Transcriptional programming and gene regulation in WC1+ γδ T cell subpopulations
Damani‐Yokota, P., Zhang, F., Gillespie, A., Park, H., Burnside, A., Telfer, J. C., & Baldwin, C. L. (2021) · Molecular Immunology · doi:10.1016/j.molimm.2021.12.016 · Cited by 8
γδ T cells: The potential role in liver disease and implications for cancer immunotherapy
Ren, H., Li, W., Liu, X., & Zhao, N. (2022) · Journal of Leukocyte Biology · doi:10.1002/jlb.5mr0822-733rrr · Cited by 7
“4 In circulating blood and lymphoid organs of healthy individuals, 50–90%of γδTcells present asVγ9Vδ2.(5) Numerous studies have shown that Vγ9Vδ2 T cells have a vital function in antitumor immunity and immune cell therapy.”
BackgroundTIGIT-expressing zoledronate-specific γδ T cells display enhanced antitumor activity
You, H., Zhu, H., Zhao, Y., et al. (2022) · Journal of Leukocyte Biology · doi:10.1002/jlb.5ma0822-759r · Cited by 7
Axl is a key regulator of intestinal γδ T‐cell homeostasis
Kim, S., Park, M. J., Yee, S., Ji, K.-Y., Lee, E., Nguyen, T., Nguyen, T. H., Jang, J. H., Kim, E., Choi, H., et al. (2019) · The FASEB Journal · doi:10.1096/fj.201901356r · Cited by 7
dos Santos, C. D. L. P., Vacani-Martins, N., Cascabulho, C. M., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.868574 · Cited by 6
The Contribution of Human Herpes Viruses to γδ T Cell Mobilisation in Co-Infections
Martini, F., & Champagne, É. (2021) · Viruses · doi:10.3390/v13122372 · Cited by 6
Wang, Q., Sun, Q., Chen, Q., Li, H., & Liu, D. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.9354 · Cited by 5
“CD27 and CD28 are two major costimulatory molecules with independent and non‐redundant roles in the activa‐ tion, proliferation and survival of γδ T cells (11,12).”
BackgroundGoes, V., Neves, R. H., Arnóbio, A., et al. (2016) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2016.06.003 · Cited by 5
Ligands for Intestinal Intraepithelial T Lymphocytes in Health and Disease
Hada, A., & Xiao, Z. (2025) · Pathogens · doi:10.3390/pathogens14020109 · Cited by 4
Phenotypic characterization of human peripheral γδT‐cell subsets in glioblastoma
Belghali, M. Y., Elmoumou, L., Hazime, R., et al. (2022) · Microbiology and Immunology · doi:10.1111/1348-0421.13016 · Cited by 4
“However, upon activation, γδT cells are known to rapidly upregulate BTLA expression.(7) The engagement of BTLA with its ligand, herpes virus entry mediator, a member of the TNFR family, attenuates γδT cell activation and differentiation.”
BackgroundMaerz, M. D., Makatsa, M. S., Bucşan, A. N., et al. (2026) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102536 · Cited by 3
“41 Therefore, we next sought to assess to what extent the V δ 1/3 T cell repertoire is modulated by IV-BCG.”
Yurova, K. A., Геннадьевна, Х. О., Дунец, Н. А., et al. (2017) · Cell and Tissue Biology · doi:10.1134/s1990519x1705011x · Cited by 3
“High expression of the surface costimulating CD27 molecule, which has its own CD70 ligand on the antigen-presenting cell, is a distinctive feature of naive lymphocytes from more mature T-cell populations (Libregts et al., 2011; van Montfrans et al., 2012; Coquet et al., 2013; Kudryavtsev, 2014; Ribeiro et al., 2015).”
BackgroundChu, T. H., Khairallah, C. F., Shieh, J., et al. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1010103 · Cited by 3
“Given that IL-12 signaling promotes STAT4 phosphorylation and IFNγ production in γδ T cells [29,93] and Yersinia spp.”
BackgroundHarnessing γδ T Cells as Natural Immune Modulators
Hedges, J. F., & Jutila, M. A. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-811924-2.00046-8 · Cited by 3
“They also express tumor necrosis factor (TNF) receptor family molecules CD27, CD30, and CD137 [9] .”
BackgroundAccumulation of γδT cells in the decidua is promoted by RANKL which upregulates ICAM-1 via NF-κB
Chang, R., Dai, J., Qiu, Y.-H., et al. (2024) · Reproduction · doi:10.1530/rep-23-0262 · Cited by 1
Castro‐Zavala, A., Nieto-Nieves, A. E., Melgar‐Locatelli, S., Medina-Rodríguez, L., Mañas‐Padilla, M. C., & Castilla‐Ortega, E. (2025) · Behavioural Brain Research · doi:10.1016/j.bbr.2025.115772 · Cited by 2
Metadata
- Authors
- Ribeiro, S. T., Ribot, J. C., & Silva-Santos, B.
- Affiliations
- University of Lisbon (PT)
- ORCID
- Ribot, Julie C.
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2015-01-26
- Volume
- 6
- Pages
- 15-15
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC4306313
- OpenAlex
- W2027271725
- Semantic Scholar
- d2d3632814aa56e04fe85192b8fcd093a630672b
- Cited by
- 116
- References
- 127
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 7 · 2023: 4 · 2022: 15 · 2021: 21 · 2020: 15 · 2019: 13 · 2018: 13 · 2017: 8 · 2016: 4 · 2015: 2
- FWCI
- 0.85
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Funders
- Fundação para a Ciência e a Tecnologia (SFRH/BD/84123/2012)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- γδ T cells, receptor signaling, T cell activation, T cell differentiation, costimulatory receptors, CD27, CD28, cytokine receptors, interleukin-2 receptor, IL-7 receptor, IL-15 receptor, NK cell receptors, NKG2D, cytotoxicity, inhibitory receptors, PD-1, BTLA, T cell homeostasis, immunotherapy
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