Beyond alphabeta/gammadelta lineage commitment: TCR signal strength regulates gammadelta T cell maturation and effector fate

Abstract

Signaling by the gammadelta T cell receptor (TCR) is required not only for alphabeta/gammadelta lineage commitment but also to activate and elicit effector functions in mature gammadelta T cells. Notably, at both of these stages, the signal delivered by the gammadeltaTCR is more robust than the one delivered by either the preTCR or the alphabetaTCR. Recent studies now provide evidence that signaling by the gammadeltaTCR is also required at other stages during gammadelta T cell development. Remarkably, the strength of the gammadeltaTCR signal also plays a role at these other stages, as evidenced by the findings that genetic manipulation of gammadeltaTCR signal strength affects gammadelta T cell maturation and effector fate. In this review, we discuss how a strong TCR signal is a recurring theme in gammadelta T cell development and activation.

Fig. 1

Current models of αβ/γδ lineage commitment. (A) Stochastic model: in this model, the lineage fate decision occurs randomly prior to the expression of either the preTCR or the γδTCR. Nonetheless, the expressed TCR isoform must match the predetermined fate of the immature thymocyte in order for that cell to mature. If the isoform does not match the predetermined fate, then the immature thymocyte undergoes apoptosis. (B) Signal strength model: in this model, the strength of the TCR signal dictates the fate of the cell, with cells receiving a strong signal choosing the γδ T cell fate and cells receiving a weak signal choosing the αβ T cell fate. In a wild-type thymus, it is usually the γδTCR that delivers a strong TCR signal and the preTCR that delivers a weak TCR signal.

Fig. 2

Proposed scenarios by which thymic γδ T cells acquire effector functions. γδ T cells acquire the potential to differentiate into effectors, which are able to produce IL-17, IFNγ or both IFNγ and IL-4, in the thymus. As it is not known whether the acquisition of effector fate occurs concurrently with or subsequent to commitment to the γδ lineage, we have designated the cell that has the potential to give rise to these different effectors by a “?”. Moreover, based on current data, we have ordered the different effector fates relative to one another according to their dependence on ligand- and cytokine-induced signaling. (A) In the first scenario, all effector fates represent different lineages, with the resulting effector fate depending on the specificity of theγδTCR in addition to the availability of self-ligands and various cytokines. (B) In the second scenario, CD27⁺ γδ thymocytes, which all have the potential to become IFNγ-producers, represent a single effector lineage that can give rise to CD122⁺ CD27⁺ γδ thymocytes following encounter with self-antigen. (C) In the last scenario, we have grouped NKT-like, CD122⁺ CD27⁺ and CD122⁻ CD27⁺ γδ subsets into one lineage based on their potential to produce IFNγ. As NKT-like and CD122⁺ CD27⁺ γδ subsets require interactions with self-antigen, we propose that it is the strength of the signal delivered by this interaction that dictates effector fate, with cells receiving the stronger signal becoming NKT-like γδ T cells.