Abstract
The integration of multiple signalling pathways that co-ordinate T cell metabolism and transcriptional reprogramming is required to drive T cell differentiation and proliferation. One key T cell signalling module is mediated by extracellular signal-regulated kinases (ERKs) which are activated in response to antigen receptor engagement. The activity of ERKs is often used to report antigen receptor occupancy but the full details of how ERKs control T cell activation is not understood. Accordingly, we have used mass spectrometry to explore how ERK signalling pathways control antigen receptor driven proteome restructuring in CD8+ T cells to gain insights about the biological processes controlled by ERKs in primary lymphocytes. Quantitative analysis of >8000 proteins identified 900 ERK regulated proteins in activated CD8+ T cells. The data identify both positive and negative regulatory roles for ERKs during T cell activation and reveal that ERK signalling primarily controls the repertoire of transcription factors, cytokines and cytokine receptors expressed by activated T cells. It was striking that a large proportion of the proteome restructuring that is driven by triggering of the T cell antigen receptor is not dependent on ERK activation. However, the selective targets of the ERK signalling module include the critical effector molecules and the cytokines that allow T cell communication with other immune cells to mediate adaptive immune responses.
Highlights
The growth, proliferative expansion and differentiation of T lymphocytes is initiated by signalling pathways regulated by the T cell antigen receptor (TCR) and balanced by positive and negative feedback signals transduced by cytokines, co-stimulatory receptors and inhibitory/immune checkpoint receptors [1]
This was supported by flow cytometry data of cell forward and side scatter, which confirmed that blocking ERK1/2 activity had only a modest impact on the estimated size of these T cells after 24 h of TCR activation (Figure 1B)
The data show that a large proportion of the proteome restructuring that is driven by triggering of the TCR is not dependent on extracellular signal-regulated kinases (ERKs)
Summary
The growth, proliferative expansion and differentiation of T lymphocytes is initiated by signalling pathways regulated by the T cell antigen receptor (TCR) and balanced by positive and negative feedback signals transduced by cytokines, co-stimulatory receptors and inhibitory/immune checkpoint receptors [1]. The initial events in TCR signalling are mediated by cytosolic tyrosine kinases and adaptors that function to couple the TCR to a network of serine–threonine kinases that propagate the signal from the cell membrane to the nucleus and drive the transcriptional and metabolic changes that support effector T cell differentiation [2]. TCR triggering rapidly causes Ras proteins to cycle from a GDP-bound (inactive) to a GTP-bound (active) state that allows Ras proteins to bind to Raf serine–threonine kinases. This drives a pathway whereby active Raf kinases phosphorylate and activate the kinases MEK1/2 which phosphorylate key threonine and tyrosine residues in ERK1/2 to activate these kinases [5,6]
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