Key Points
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Six properties may collectively distinguish γδ T cells from αβ T cells, and thereby define their unique contributions to lymphocyte biology.
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One, γδ T cell receptors (TCRs) recognize a broad set of antigens. Although only a few γδ TCR ligands have been identified so far, they belong to diverse families of exogenous molecules and autoantigens (such as self or non-self proteins, lipids and phosphorylated isoprenoids), which underlines the capacity of these cells to respond to both foreign pathogens and stressed self.
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Two, γδ T cells are rapid responders. γδ T cells, which mature in the thymus, do not require further peripheral maturation or extensive clonal expansion to initiate terminal effector functions. In addition to their diversified and localized distribution, they are well suited to provide a first line of defence in many tissues. The diversity of the antigen receptors that they express provides them with the potential to sense a greater variety of insults than can be sensed by dendritic cells.
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Three, γδ T cells are developmentally pre-programmed. Unlike conventional αβ T cells, many γδ T cells acquire their functional effector phenotypes during development in the thymus, thereby facilitating fast responsiveness. Some functions, such as antigen presentation, are not functions associated with conventional αβ T cells. Recent developments point to specific molecular networks that drive pre-programming and that are strongly influenced by the strength of TCR signalling.
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Four, γδ T cells predominantly reside in specific tissues. This distribution may originate via the selective expression of specific chemokine receptors, but the retention of these cells in tissues may reflect a steady-state engagement of tissue-specific ligands by particular pairs of TCR variable regions.
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Five, γδ T cells have a broad contribution to immune responses. The large range of soluble factors produced by γδ T cells, and their potential to interact with and regulate most of the major immune cell subsets, are consistent with emerging evidence that γδ T cells have a key central role in many aspects of immunobiology and immunopathology.
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Six, γδ T cells mediate crucial responses to specific pathogens. γδ T cells seem to be specialized in the defence of the host against a specific set of pathogens, including cytomegalovirus, Mycobacterium tuberculosis and Plasmodium falciparum. This might supplement the short-comings of conventional adaptive immune cells, particularly during early life.
Abstract
γδ T cells are a unique and conserved population of lymphocytes that have been the subject of a recent explosion of interest owing to their essential contributions to many types of immune response and immunopathology. But what does the integration of recent and long-established studies really tell us about these cells and their place in immunology? The time is ripe to consider the evidence for their unique and crucial functions. We conclude that whereas B cells and αβ T cells are commonly thought to contribute primarily to the antigen-specific effector and memory phases of immunity, γδ T cells are distinct in that they combine conventional adaptive features (inherent in their T cell receptors and pleiotropic effector functions) with rapid, innate-like responses that can place them in the initiation phase of immune reactions. This underpins a revised perspective on lymphocyte biology and the regulation of immunogenicity.
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Acknowledgements
We thank many colleagues, within our laboratory and beyond it, including B. Silva-Santos, J. Kisielow, P. Fisch, L. Lefrancois, R. Tigelaar and W. Born, for thoughtful input and clarification of data, and we thank the Wellcome Trust and Cancer Research UK for funding. We apologize to those whose findings we may have inadvertently overlooked or that were a victim of space constraints.
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Glossary
- V(D)J recombination
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The somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antigen receptors, leading to repertoire diversity of both B cell and T cell receptors.
- Dendritic epidermal γδ T cells
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(DETCs). γδ T cell receptor (TCR)-expressing cells selectively localized in the epidermis that have been described in rodents and cattle but not in humans. In mice, essentially all DETCs express precisely the same TCR, forming a prototype lymphocyte repertoire of limited diversity.
- Non-obese diabetic mice
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(NOD mice). An inbred strain of mice that spontaneously develop T cell-mediated autoimmune diabetes, which is dependent on their expression of the MHC class II molecule I-Ag7.
- B-1 cells
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IgMhiIgDlowMAC1+B220lowCD23− cells that are dominant in the peritoneal and pleural cavities. Their precursors develop in the fetal liver and omentum, and in adult mice the size of the B-1 cell population is kept constant owing to the self-renewing capacity of these cells. B-1 cells recognize self components, as well as common bacterial antigens, and they secrete antibodies that tend to have a low affinity and a broad specificity.
- Lymphoid stress-surveillance
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The capacity of lymphocytes, as opposed to myelomonocytic cells, to sense infection or tissue dysregulation and to respond rapidly, in synchrony with innate responses.
- NKG2D
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(Natural killer group 2, member D). A lectin-type activating receptor expressed by most NK cells and NKT cells, by many γδ T cells and by antigen-experienced cytolytic CD8+ αβ T cells. NKG2D in humans recognizes MHC class I polypeptide-related sequence A (MICA) and MICB, and at least four related ULBP family proteins, and in mice recognizes multiple members of the structurally related retinoic acid early transcript 1 (RAE1) and H60 families and MULT1. Such ligands are generally expressed at the surface of infected, stressed or transformed cells.
- Stress antigens
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Molecules, such as MICA and RAE1, that are upregulated by cellular dysregulation and are recognized by lymphocytes as part of a process of immune surveillance.
- Signals 1, 2 and 3
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Cell signalling pathways that are activated by the engagement of the antigen receptor (signal 1), co-stimulatory receptors such as CD28 (signal 2) and cytokine receptors such as the interleukin-2 receptor (signal 3).
- Anergic
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A state in which a T cell is almost completely non-responsive to TCR engagement. This may occur when a peripheral T cell is exposed to an antigen in the absence of co-stimulation, and it is interpreted as a means to suppress potentially autoreactive T cell responses in the absence of infection.
- Intraepithelial lymphocytes
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(IELs). T cells that reside in the basolateral side of an epithelium, above the basement membrane. They express either an αβ TCR or a γδ TCR, and in the murine gut they frequently express the CD8αα homodimer rather than the CD8αβ heterodimer that is expressed by conventional CD8+ T cells in the lymph nodes and by another subset of IELs. It has been proposed that CD8αα+ IELs are self-reactive, TCR agonist-selected cells that have regulatory properties.
- Germinal centres
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Highly specialized and dynamic microenvironments that give rise to secondary B cell follicles during an immune response. They are the main site of B cell maturation, leading to the generation of memory B cells and plasma cells that produce high-affinity antibodies.
- Leaky mutation
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A mutation that results in partial rather than complete inactivation of the wild-type function.
- Autoimmune regulator
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(AIRE). A transcription factor that is expressed by medullary thymic epithelial cells (mTECs) and promotes the promiscuous expression of genes that are otherwise specific to individual peripheral tissues. Peptides derived from these tissue-specific antigens are presented by mTECs to developing αβ T cells, and any T cells with high-affinity TCRs may be clonally deleted as a means of central tolerance.
- MRL–lpr mice
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A mouse strain that spontaneously develops glomerulonephritis and other symptoms of systemic lupus erythematosus (SLE). The lpr mutation causes a defect in CD95 (also known as FAS), preventing the apoptosis of activated lymphocytes. The MRL strain contributes disease-associated mutations that have yet to be identified.
- Imiquimod
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An imidazoquinoline-based compound that is sensed by TLR7. It is currently used for the treatment of basal cell carcinoma, but it has also been implicated in iatrogenic induction of psoriasis-like symptoms.
- Autoinflammatory diseases
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Diseases that are characterized by seemingly unprovoked pathological activation of the innate immune system in the absence of overt autoantibodies or autoreactive T cells.
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Vantourout, P., Hayday, A. Six-of-the-best: unique contributions of γδ T cells to immunology. Nat Rev Immunol 13, 88–100 (2013). https://doi.org/10.1038/nri3384
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DOI: https://doi.org/10.1038/nri3384
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