There are two fundamentally distinct T cell lineages: αβ and γδ T cells. Individual lineage specification occurs in the thymus. This Review discusses recent findings that shed light on the factors that regulate this process, focusing on evidence that supports a central role for T cell receptor (TCR)-derived signals and thymus microenvironmental cues in mediating γδ T cell lineage choice and development.
Over the past two decades, two models have been proposed to account for the differences seen in γδ and αβ T cell commitment, namely lineage 'instruction' by cognate TCR expression and TCR-independent lineage 'pre-commitment' followed by selection. Rigid adherence to either of these models is not supported by the available data.
We present recent evidence that supports a 'TCR signal strength' model in which quantitatively larger TCR-mediated signals are proposed to favour γδ T cell lineage development. Specifically, the induction of inhibitor of DNA binding 3 (ID3) by strong TCR signals downstream of the extracellular signal-regulated kinase (ERK)–early growth response (EGR) pathway seems to be a crucial mechanism by which the γδ T cell lineage is instructed. Interestingly, ID3 is required for both the development of a normal repertoire of γδ T cells and for limiting the development of γδ T cell subsets that express high-affinity, autoreactive TCRs.
Although TCR-mediated signals seem to have the greatest impact on γδ versus αβ T cell specification, signals from the thymus microenvironment — for example, Notch ligands, lymphotoxin-mediated trans-conditioning and TCR ligands — also contribute to lineage and/or functional diversification.
Given the emerging understanding of the important roles that γδ T cells have in immune regulation, maintenance of tissue integrity and inflammation, future studies examining the acquisition of these functions will be of great interest.
The thymus produces several types of functionally distinct T cell subsets. However, at a more fundamental level only two genetically distinct T cell lineages exist: the γδ and αβ T cell lineages. Precisely how these two T cell lineages are generated from common thymocyte progenitor cells remains to be fully elucidated and is under intense investigation. Here, we highlight recent findings that have helped to provide important clues to the mechanisms that underpin the generation of γδ T cells in the mouse thymus.
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This work was supported by a grant from the Canadian Institutes of Health Research (CIHR-MOP42387). J.C.Z.-P. is supported by a Canada Research Chair in Developmental Immunology.
The authors declare no competing financial interests.
- Gene rearrangement
The ordered rearrangement of variable regions of genes encoding antigen receptors. This rearrangement contributes to increased receptor diversity.
- Pre-T cell receptor
(Pre-TCR). A receptor that is expressed by pre-T cells. It is formed by a T cell receptor-β (TCRβ)-chain paired with a surrogate TCRα-chain (known as the invariant pre-Tα protein). The receptor complex includes CD3 proteins and transduces signals that allow further T cell development.
The controlled developmental transition beyond the double-negative 3 (DN3) stage to the double-positive (DP) stage that is limited to T cells that have successfully rearranged their T cell receptor-β (TCRβ)-chain genes to express a functional cell surface pre-TCR. The conditional developmental arrest encountered at the DN3 stage is termed the β-selection checkpoint.
- Signal strength
The overall amount of signal emanating from the T cell receptor (TCR), which is typically assessed by monitoring phosphorylation events in signalling cascades downstream of the TCR. This is affected by the concentration of antigen, the extent of signal amplification by co-stimulatory molecules and the duration of the antigen-presenting cell–T cell immune synapse. These parameters can vary widely and in a stochastic manner.
A signalling system comprised of highly conserved transmembrane receptors that regulate cell-fate choice in the development of many cell lineages and so are vital in the regulation of embryonic differentiation and development.
- Recombinase-activating genes
Genes that are expressed by developing lymphocytes. Mice that lack either recombinase-activation gene 1 (Rag1) or Rag2 fail to produce B or T cells owing to a developmental block in the gene rearrangement that is necessary for receptor expression.
- KN6 γδ TCR-transgenic mice
Mice that express the γδ T cell receptor (TCR) transgene (Vγ4–Vδ5), which is positively selected on the MHC class Ib molecule T10d, but is deleted by the higher affinity T10b and/or T22b ligands.
- Dendritic epidermal T cells
(DETCs). γδ T cell receptor (TCR)+ cells that specifically localize in the epidermis and are present in rodents and cattle but not in humans. In mice, essentially all DETCs express the same Vγ5–Vδ1 TCR, forming a prototype lymphocyte repertoire of limited diversity.
(LT). A protein that belongs to the tumour necrosis factor family and that can be produced as a secreted homotrimer, lymphotoxin-α3 (LTα3), or as a membrane-bound heterotrimer, LTα1β2. The heterotrimer LTα1β2 binds to the lymphotoxin-β receptor (LTβR).
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Ciofani, M., Zúñiga-Pflücker, J. Determining γδ versus αβ T cell development. Nat Rev Immunol 10, 657–663 (2010). https://doi.org/10.1038/nri2820
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