Temporal Predisposition to αβ and γδ T Cell Fates in the Thymus

Abstract

How T cell progenitors engage into the γδ or αβ T cell lineages is a matter of intense debate. In this study, we analyzed the differentiation potential of single thymocytes from wild-type and TCRγδ-transgenic mice at two sequential early developmental stages. Double-negative (DN) 3 progenitors from both wild-type and transgenic mice retain the capacity to engage into both pathways, indicating that full commitment is only completed after this stage. More importantly, DN2 and DN3 progenitors from TCRγδ transgenic mice have strong biases for opposite fates, indicating that developmentally regulated changes, other than the production of a functional TCR, altered their likelihood to become a γδ or an αβ T cell. Thus, unlike the differentiation in other hematopoietic lineages, T cell progenitors did not restrict, but rather switch their differentiation potential as they developed.

Critical Role of TCR Specificity in the Development of Vγ1Vδ6.3+ Innate NKTγδ Cells

“…Furthermore, the PLZF + gd thymocyte subset was severely reduced in TCRd 2/2 Tg-gd mice, demonstrating a strict requirement for a Vg1/Vd6.3 (or other selectable TCR) for the development of a sizable population of PLZF + gd T cells. This is unlikely due to global alterations in the development of gd T cells in the Tg-gd mice because both mRNA and protein expression of the transgenes parallels that of endogenous TCRg and TCRd chains in WT animals (24,26). The expression of the correct TCR is not only necessary for the development of the PLZF + gd thymocytes but it also appears to be sufficient as suggested by the fact that a Tg line expressing Vg1/Vd6.4 TCR transgenes (isolated from a NKTgd hybridoma; see Supplemental Table I) in a Rag-1 2/2 background developed large numbers of PLZF + T cells (10).…”

Conditional Deletion of the V-ATPase a2-Subunit Disrupts Intrathymic T Cell Development

“…Progression of progenitor cells from the DN1 to later stages is dependent on a confluence of factors that sequentially restrict and redirect the divergence of other lineages during development (39, 40). γδ T cells arise during the DN2 and DN3 stages of intrathymic development, ostensibly prior to β-selection, while NKT cells emerge from the DP pool following rearrangement of TCRβ and α chains (41, 42).…”

Direct regulation of TCR rearrangement and expression by E proteins during early T cell development

“…Several patterns of TCR receptor rearrangement can occur in DN thymocytes, leading to four distinct outcomes (Margolis et al, 1997). In most thymocytes, rearrangement of the TCRγ and TCRδ loci occur at the DN2 stage before rearrangement of the TCRβ locus at the DN3 stage (Capone et al, 1998; Livak et al, 1999; Pereira et al, 2012; Shibata et al, 2014). Cells that successfully express and receive a signal through the γδTCR can enter the γδ T cell lineage (Figure 1a).…”

“…Concurrent expression of pre‐TCR and γδTCR can boost the weak γδTCR signal enough to direct the cells into the γδ T cell lineage (Zarin et al, 2014). In these cases, pre‐TCR‐specific components are downregulated and TCRβ expression is lost, resulting in γδ T cells with residual TCRβ locus rearrangements (Margolis et al, 1997; Pereira et al, 2012) (Figure 1b). If the TCRγ and TCRδ rearrangements are non‐productive and a γδTCR is not expressed on the surface, this leads to the normal course of β‐selection and generation of αβ T cells that carry out‐of‐frame TCRδ and/or TCRγ rearrangements (Figure 1c).…”