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Six-of-the-best: unique contributions of γδ T cells to immunology - PubMed

Review

Six-of-the-best: unique contributions of γδ T cells to immunology

Pierre Vantourout et al. Nat Rev Immunol. 2013 Feb.

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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Figures

Figure 1
Figure 1. Overview of pre- and post-natal γδ T cell development

Top: Mouse γδ T cell development from foetal liver progenitors. Cells undergo development through several steps of differentiation, starting at the double negative 1 (DN1) stage characterized by a CD44+ CD25− phenotype, followed by the CD44+CD25+ DN2 stage. At this point, the β, γ and δ chains of the TCR are rearranged. A functional γδ TCR expression will drive cells into the γδ lineage, supported by the expression of Sox13. Cells failing to produce a functional γδ TCR will undergo β selection supported by Notch 1, with a further rearrangement of the TCR α chain, eventually entering the Double Positive (DP) stage. These cells can support γδ T cell development via trans-conditioning (green arrow). Unlike αβ T cells, γδ T cells are functionally pre-programmed, depending on TCR and/or related signalling. It is proposed that a strong, agonist-dependent signal will result in the loss of Sox13 and expression of NFAT, NFκB, Egr3 and Tbet, and a capability to produce IFN-γ among other effector molecules while weaker TCR signalling permits the cells to maintain Sox13, increase Rorγc expression, and a adopt an IL-17 “default position”. The dashed line indicates the potential origin of γδ cells from progenitors with either a DN3 or DN4 phenotype. The curved arrows indicate the potential for lifelong self-renewal that exists in at least two pre-natally derived γδ cell compartments. Bottom: Mouse post-natal development from bone marrow-derived progenitors. There is no evidence that innate-like CD27− IL-17-producing γδ T cells can be generated from the bone marrow, implying that a different thymic progenitor gives rise to post-natal γδ T cells, by comparison to foetus-derived γδ cells. With no evidence for IL-17-competent progenitors, the evidence for pre-programming is less, and naïve unprimed cells may emerge in the periphery, possibly with a “default potential” for IFN-γ production.

Figure 2
Figure 2. An alternative way to achieve broad systemic immune responses

(A) The text-book view of the activation of an adaptive immune response. Dendritic cells (DC) capture pathogens and mature while migrating to the lymph nodes, where they prime αβ T and B cells which will migrate back to the infected tissue and mount effector responses or produce antibodies, respectively. This very specific albeit slow response is complemented by γδ T cells which, in response to various sources of stress, not only mount immediate, local effector responses but also trigger the other arms of the adaptive immune system (B).

Figure 3
Figure 3. Six of the best γδ T cell functions

An increasing body of literature now demonstrates that γδ T cells can play an important central role in defending the organism against a broad range of infectious and sterile stresses by directly eliminating infected or stressed cells; by producing a diversified set of cytokines and chemokines to regulate other immune and non-immune cells; by directly promoting immune cell maturation and activation by triggering B cell help, DC maturation and αβ T cell priming via antigen presentation; and finally by regulating stromal cell function.

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