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  • Review Article
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γδ T cell effector functions: a blend of innate programming and acquired plasticity

Nature Reviews Immunology volume 10, pages 467–478 (2010)Cite this article

Subjects

Key Points

  • Effector functions of γδ T cells influence the outcome of the host responses to infections, injury and malignancy, and they have a role in the pathology of allergic and autoimmune diseases. Although γδ T cells share functional features with other cells of the immune system, specialization of γδ T cell subsets and the timing and tissue localization of their functional engagement makes their responses unique.

  • Effector functions of the γδ T cell subsets develop under the influence of innate programming and environmental signals. Programming during thymocyte maturation restricts the functional potential of populations of γδ T cells expressing given T cell receptors (TCRs) but they retain some degree of functional plasticity that is influenced by the context of an ongoing immune response.

  • The γδ T cells interact with a wide range of cell types, including innate immune cells, T cells and B cells, as well as non-immune tissue cells. Such interactions might trigger regulatory and cytotoxic responses of γδ T cells, they also induce innate and adaptive immunity, and they can promote tissue repair and wound healing.

  • Although studies in mice have been useful in identifying possible roles for γδ T cells in vivo, several differences between mouse and human subsets limit the translation of these findings to human γδ T cells. Nevertheless, comparison of functionally analogous subsets in both species is expected to provide insight into the immunobiology of human γδ T cells.

  • Clinical-grade compounds that mediate human γδ T cell activation have been shown to accelerate pathogen clearance and tissue repair in bacterial and viral infections, and such treatments correlate with disease stabilization or tumour regression in patients with malignancies.

  • A key remaining challenge for future study is the γδ TCR itself, of which the precise mode of action and role in the development and triggering of γδ T cell effector functions remains poorly understood.

Abstract

γδ T cells have several innate cell-like features that allow their early activation following recognition of conserved stress-induced ligands. Here we review recent observations revealing the ability of γδ T cells to rapidly produce cytokines that regulate pathogen clearance, inflammation and tissue homeostasis in response to tissue stress. These studies provide insights into how they acquire these properties, through both developmental programming in the thymus and functional polarization in the periphery. Innate features of γδ T cells underlie their non-redundant role in several physiopathological contexts and are therefore being exploited in the design of new immunotherapeutic approaches.

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Figure 1: Sensing of cellular stress and infection by γδ T cells.
Figure 2: Functional programming of invariant or invariant-like γδ T cell subsets.
Figure 3: Cellular interplay involving γδ T cells.
Figure 4: T cell–dendritic cell interactions in a normal mouse lung.

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Acknowledgements

We thank H. Sicard (Innate Pharma, Marseilles, France) for helpful suggestions, Z. Yin (Yale School of Medicine, New Haven, Connecticut, USA) for personal communication and J. M. Wands (NJH, Denver, Colorado, USA) for the image used in figure 4.

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Authors and Affiliations

  1. Institut National de la Sant et de la Recherche Mdicale (INSERM) U892, IRT UN, 8 quai Moncousu, BP 70721, 44007, Nantes cedex 1, France

    Marc Bonneville

  2. Integrated Department of Immunology, National Jewish Health and University of Colorado, Denver, 80206, Colorado, USA

    Rebecca L. O'Brien & Willi K. Born

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  1. Marc Bonneville
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Correspondence to Marc Bonneville or Willi K. Born.

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Marc Bonneville is a founder scientist of the company Innate Pharma, which has been developing immunotherapeutic approaches targeting γδ T cells. Some of such immunotherapeutic trials are mentioned in the Review.

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Glossary

Pattern recognition receptor

(PRR). A host receptor (such as Toll-like receptors (TLRs) or NOD-like receptors (NLRs)) that can sense pathogen-associated molecular patterns and initiate signalling cascades that lead to an innate immune response. These can be membrane bound (such as TLRs) or soluble cytoplasmic receptors (such as retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and NLRs).

Conventional αβ T cell

A T cell subset specific for peptide antigens that are presented by polymorphic MHC class I molecules (HLA-A, HLA-B, HLA-C in humans, H–2K, H–2D, H–2L in mice) or MHC class II molecules (HLA-DP, HLA-DQ, HLA-DR in humans, I–E or I–A in mice).

Invariant NKT cell

(iNKT cell). Lymphocytes that express a particular variable gene segment, Vα14 (in mice) and Vα24 (in humans), precisely rearranged to a particular Jα gene segment to yield T cell receptor α-chains with an invariant sequence. Typically, these cells express memory T cell markers and NK cell receptors, are enriched in the liver, are activated by recognition of CD1d (particularly when bound with α-galactosylceramide) and readily produce IL-2, IL-4, IL-13 and IFNγ.

Mucosa-associated invariant T cell

(MAIT cell). A conserved mammalian T cell subset expressing TCR α-chains with a canonical Vα7.2 junctional sequence in rodents and humans. MAIT cells are specific for an as yet undefined antigen that is bound to the monomorphic MHC class I-related MR1 product. Similar to iNKT cells, MAIT cells frequently express memory T cell markers and NK cell receptors, but differ from iNKT cells by their tropism for intestinal rather than liver tissues.

Pathogen-associated molecular pattern

(PAMP). Conserved motifs recognized by PRRs that are broadly expressed by various classes of microorganisms but absent from mammals. Examples include lipoteichoic acid (in Gram-positive bacteria), lipoarabinomannan (in mycobacteria), dextran (in fungi), lipopolysaccharide (in Gram-negative bacteria), double-stranded RNA (in viruses) and CpG DNA (in bacteria).

Danger-associated molecular pattern

(DAMP). A conserved mammalian motif, recognized by PRRs, that is broadly upregulated in response to cellular stress. Examples include heat shock proteins, high motility group box 1 protein (HMGB1), DNA-bending proteins and uric acid.

Natural killer receptors

(NKRs). Receptors initially identified on NK cells and later shown to be expressed by some memory T cells as well. NKRs are either related to immunoglobulins (such as killer immunoglobulin-like receptors (KIRs) or to C-type lectins (such as NKRP1 or CD94–NKG2). Some NKRs (such as the KIRS gene products) deliver activating signals whereas others (such as the MHC class I-specific KIRLl gene products) deliver inhibitory signals.

Natural killer group 2, member D

(NKG2D). An activating lectin-like receptor expressed by most NK cells, CD8+ αβ T cells and γδ T cells. NKG2D is specific for different MHC class I-related ligands that may be upregulated on activated, transformed or virus-infected cells, such as members of the retinoic acid early transcript 1 (RAE1) and cytomegalovirus UL16-binding protein (ULBP) families in rodents and humans, or the MHC class polypeptide-related sequence A (MICA) and MICB in humans.

NOD-like receptors

(NLRs). A family of cytoplasmic PRRs that trigger immune responses against microbial threats. For example, NLRP3 senses microbial ligands, endogenous danger signals and certain crystalline substances, and it initiates the assembly of the NLRP3 inflammasome. 22 human and 34 mouse NLR genes have been identified.

Chronic granulomatous disease

(CGD). A human primary immunodeficiency syndrome associated with hyperinflammation and increased susceptibility to bacterial and fungal infections.

Allergic airway hyperresponsiveness

(Allergic AHR; also known as bronchial hyperresponsiveness). A state characterized by easily triggered bronchospasm (contraction of the small airways). AHR is a hallmark of asthma, and it occurs frequently in individuals with chronic obstructive pulmonary disease. It can be induced in mice by allergen sensitization and challenge or by airway exposure to environmental triggers such as ozone. Bronchial challenge with nonspecific agents such as methacholine or histamine is used as a test for AHR.

Antibody-dependent cell cytotoxicity

(ADCC). A cytotoxic mechanism mediated by engagement of low-affinity receptors for the constant fragment of IgG (FcγRIII; also known as CD16) by antibody-coated target cells.

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Bonneville, M., O'Brien, R. & Born, W. γδ T cell effector functions: a blend of innate programming and acquired plasticity. Nat Rev Immunol 10, 467–478 (2010). https://doi.org/10.1038/nri2781

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