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Abstract
CD4(+)CD8(+) “double positive” (DP) thymocytes differentiate into diverse αβ T cell sub-types using mechanistically distinct programs. For example, conventional αβ T cells develop from DP cells after partial-agonist T cell receptor (TCR) interactions with self-peptide/MHC, whereas unconventional αβ T cells, such as TCRαβ(+)CD8αα(+) intraepithelial lymphocytes (IELs), require full-agonist TCR interactions. Despite this, DP cells appear homogeneous, and it remains unclear how distinct TCR signalling instructs distinct developmental outcomes. Moreover, whether TCR signals at earlier stages of development, for example in CD4(−)CD8(−) double negative (DN) cells, impact on later fate decisions is presently unknown. Here, we assess four strains of mice that display altered TCR signal strength in DN cells, which correlates with altered generation of unconventional TCRαβ(+)CD8αα(+) IELs. FVB/n mice (compared to C57BL/6 animals) and mice with altered preTCRα (pTα) expression, both displayed weaker TCR signalling in DN cells, an inefficient DN-to-DP transition, and reduced contribution of TCRαβ(+)CD8αα(+) IELs to gut epithelium. Conversely, TCRαβ(+)CD8αα(+) IEL development was favoured in mice with increased TCR signal strength in DN cells. Collectively, these data suggest TCR signal strength in DN cells directly impacts on subsequent DP cell differentiation, fundamentally altering the potential of thymocyte progenitors to adopt conventional versus unconventional T cell fates.
Highlights
The developmental origins of TCRαβ(+)CD8αα(+) intraepithelial lymphocytes have long been debated
Surface CD25 was elevated on DN3 cells from pTαa. pTα−/− animals, compared to WT (Fig. 3D), while newly selected proliferating CD71(+) DN3 cells displayed markedly less CD5, indicative of weaker TCR signalling (Fig. 3E)
This evidence of an inefficient DN3-to-DN4 transition in pTαa. pTα−/− mice correlated with a notable absence of unconventional TCRαβ(+)CD8αα(+) IELs in the small intestine (Fig. 3F) (total IEL cell yield was not significantly different between the three strains (Sup Figure S4A))
Summary
The developmental origins of TCRαβ(+)CD8αα(+) intraepithelial lymphocytes have long been debated. The recognition that TCRαβ(+)CD8αα(+) IELs, but not TCRαβ(+)CD8αβ(+) IELs, were present in athymic mice led to suggestion of their extra-thymic generation in gut lymphoid structures called cryptopatches (CPs)[6]. CPs were shown to contain CD25(+)IL-7Rα(+)c-kit(+) progenitors that could reconstitute the T cell compartments of irradiated T cell-deficient animals[26]. That athymic mice have only 5–10% of the total TCRαβ(+)CD8αα(+) IELs of euthymic mice argued for a predominately thymic origin. The thymic generation of TCRαβ(+)CD8αα(+) IELs was further supported by fate mapping experiments in which a GFP marker was activated by RORγt-promoter-driven Cre protein[7]. As all γδ T cells develop from DN cells, TCRγδ(+) IELs were GFP(−). TCRαβ(+)CD8αα(+) IELs were GFP(+), suggesting their development through a DP stage
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