Novel Insights into Gamma Delta T Cells (γδ T Cells): Receptors, Molecular Targets, and Therapeutic Potentials

Dear Colleagues,

γδ T cells were discovered about forty years ago [1,2], adding, rather unexpectedly, to the family of immunocytes expressing rearranging immune receptors, which previously had only included B cells and αβ T cells. Thousands of scientific reports published since their discovery indicate that this newest addition, i.e., T cells bearing γδ T cell receptors (TCR), express a diverse functional repertoire, enabling them to have unique roles in the orchestrated restoration of disrupted tissue homeostasis induced by infection, autoimmunity and cancer. Furthermore, γδ T cells straddle innate and adaptive immunity, as they display innate and adaptive non-major histocompatibility complex (MHC)-restricted TCR as well as non-TCR-mediated anti-tumoral cytotoxicity, produce tissue-protective as well as immune-potentiating cytokines, and display an ability to penetrate and persist, as resident T cells, in non-lymphatic, healthy and tumoral tissues [3]. These cells, however, remain the most enigmatic arm of the cellular adaptive immune system. This conundrum relates to a comprehensive definition of target antigens and modes of recognition by the γδ TCR, which, in contrast to αβ T cells, do not involve peptide fragments presented by MHC molecules [4]. Even recent groundbreaking discoveries, including the discovery of butyrophilins as mediators of innate cognitive responses of Vγ9δ2+ TCR to “phosphoantigens” of bacteria and eukaryotic cells, and the cognitive interactions of “Vδ2-negative” γδ TCR with target-cell surface expression of MHC-like molecules including CD1, endothelial cell protein C receptor (EPCR) and major histocompatibility complex class I-related gene protein (MR1) and examples of lipid antigens presented by CD1, do not clearly rationalize the enormous potential diversity of rearranged γ and δ TCR genes available to construct the γδ heterodimeric TCR. Despite this lack of clarity, the current state of knowledge has already enabled the application of the well-established characteristics of γδ T cells mentioned above in the development of novel forms of promising immunotherapy for cancer and infectious diseases.

The collection of articles in the current issue, entitled “Novel Insights into Gamma Delta T Cells (γδ T Cells): Receptors, Molecular Targets, and Therapeutic Potentials”, represents a platform for researchers to contribute to the rapidly expanding field of γδ T cell research. This issue welcomes original research, reviews and brief reviews pertaining to all aspects of γδ T cells. We are confident that these publications will enhance our understanding of this fascinating set of lymphocytes, impact the field of basic and clinical research and yield rich dividends in the future.

1. Bank I, DePinho RA, Brenner MB, Cassimeris J, Alt FW, Chess L. A functional T3 molecule associated with a novel heterodimer on the surface of immature human thymocytes. Nature. 1986, 322(6075), 179-81.
2. Brenner MB, McLean J, Dialynas DP, Strominger JL, Smith JA, Owen FL, et al. Identification of a putative second T-cell receptor. Nature. 1986, 322(6075), 145-9.
3. Ribot JC, Lopes N, Silva-Santos B. gammadelta T cells in tissue physiology and surveillance. Nat Rev Immunol. 2021, 21(4), 221-32.
4. Gully BS, Rossjohn J, Davey MS. Our evolving understanding of the role of the gammadelta T cell receptor in gammadelta T cell mediated immunity. Biochem Soc Trans. 2021, 49(5), 1985-95.

Prof. Dr. Ilan Bank
Guest Editor

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