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Abstract
SummaryExtracellular signal-regulated kinase (ERK) plays critical roles in T cell development in the thymus. Nevertheless, the dynamics of ERK activity and the role of ERK in regulating thymocyte motility remain largely unknown due to technical limitations. To visualize ERK activity in thymocytes, we here developed knockin reporter mice expressing a Förster/fluorescence resonance energy transfer (FRET)-based biosensor for ERK from the ROSA26 locus. Live imaging of thymocytes isolated from the reporter mice revealed that ERK regulates thymocyte motility in a subtype-specific manner. Negative correlation between ERK activity and motility was observed in CD4/CD8 double-positive thymocytes and CD8 single-positive thymocytes, but not in CD4 single-positive thymocytes. Interestingly, however, the temporal deviations of ERK activity from the average correlate with the motility of CD4 single-positive thymocytes. Thus, live-cell FRET imaging will open a window to understanding the dynamic nature and the diverse functions of ERK signaling in T cell biology.
Highlights
In the immune system the thymus plays a central role as the primary lymphoid organ for the development and differentiation of T cells (Lancaster et al, 2017; Miller, 2014; Nadia and Robey, 2016)
The strength of Extracellular signal-regulated kinase (ERK) activity correlates negatively with cell motility in both the DP and CD8-SP subsets, whereas temporal deviations of ERK activity correlate with cell motility in the CD4-SP subset. These results suggest that cell motility of CD4-SP is more sensitive to ERK activity dynamics compared with the motility of other subsets under physiological conditions
The live-cell fluorescence resonance energy transfer (FRET) imaging of ERK activity will open a window to understanding the dynamic nature and the diverse functions of ERK signaling in T cell biology
Summary
In the immune system the thymus plays a central role as the primary lymphoid organ for the development and differentiation of T cells (Lancaster et al, 2017; Miller, 2014; Nadia and Robey, 2016). Thymocyte maturation is a dynamic process that takes place in two distinct spatial compartments of the thymus, the cortex and the medulla. Thymocytes migrate through these compartments and engage in cellular interactions essential for their differentiation into functional and self-tolerant T cells (Penit and Vasseur, 1988). The thymic cortex harbors immature CD4/CD8 double-positive (DP) thymocytes expressing a stochastically rearranged T cell receptor (TCR). A fraction of DP thymocytes successfully receive TCR-activating signals for their positive selection through interaction with major histocompatibility complex (MHC) molecules on cortical thymic epithelial cells (TECs) (Savage and Davis, 2001). The commitment to the CD4-SP and CD8-SP subsets depends on TCR interaction with MHC classes II and I, respectively (Teh et al, 1988)
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