Alphabeta versus gammadelta lineage choice at the first TCR-controlled checkpoint

Abstract

Alphabeta and gammadelta T cells develop in the thymus from a common precursor. Although lineages initially were defined by the type of TCR they express, it soon became clear that the TCR type per se does not play a deterministic role in the lineage decision, since in various transgenic and knockout models, as well as in a small fraction of cells in wt mice, the TCRgammadelta can drive the differentiation of alphabeta lineage cells and the TCRalphabeta can drive differentiation of gammadelta lineage cells. Thus until recently it was unclear what determines lineage choice and at which stage the two lineages diverge. Recent observations suggest that TCR signal strength determines lineage fate and that lineage choice is made at or shortly after the first TCR-controlled checkpoint. While it is clear that the decision between alphabeta and gammadelta lineages is made at the first TCR-controlled checkpoint and the alphabeta sublineages split off later, it is less clear whether gammadelta sublineages divert already at the first TCR-controlled checkpoint or later. Recent experiments support the former view.

Figure 1. Lineages and TCR expression

In a wt mouse the majority of αβ lineage cells are initially driven by the pre-TCR which in case of a productive Tcra rearrangement is later replaced by the TCRαβ at the DP stage, whereas γδ lineage differentiation correlates well with TCRγδ expression. However, small populations in wt mice that are exaggerated in various knock-out and transgenic models do not follow these rules. Early TCRαβ expression can lead to the development of γδ lineage-like cells which avoid progression through the DP stage, whereas both TCRαβ and TCRγδ expression can support progression to the DP stage and thus αβ lineage differentiation in the absence of a pre-TCR. We speculate that these ‘non-canonical’ pathways might in fact be mainstream in the species that lack a pre-TCR.

Figure 2. Evolution of TCRs and lineages

The four TCR chains are present in all vertebrates that undergo Rag-dependent rearrangement. It is not clear when the molecular programs corresponding to αβ and γδ lineages were always present, but the DP stage can be found in Xenopus, suggesting that certain features of the αβ lineage existed before the split between amphibians and reptiles. pTα homologs, however, can be found only in mammals, suggesting that αβ lineage differentiation initially did not rely on pre-TCR signaling. (mya – million years ago)

Figure 3. Possible role of E-protein activity inhibition in αβ versus γδ lineage choice

Strong TCR signals lead to potent inhibition of E-protein activity through strong induction of Id3, possibly via the Erk-Egr1 axis, which favors γδ lineage differentiation. Weaker TCR signals lead to weaker Id3 induction which in turn results in less profound inhibition of E-protein function and commitment to the αβ lineage. The dependence of αβ lineage development on strong Notch signaling might in this scenario be explained by the capability of Notch to further inhibit E-proteins (in Id3-dependent or independent manner).

Figure 4. Two models of the lineage split at the first TCR-dependent checkpoint

A. TCR signaling leads to the execution of αβ or γδ lineage-specific molecular programs. At a later developmental stage sublineage-specific programs are initiated. B. TCR signaling, possibly in cooperation with other pathways, leads to the lineage split between the αβ lineage and several independent γδ lineages which do not share a common γδ molecular program.