A rate-limiting process: T cell activation from a single-cell perspective
Cytotoxic T lymphocytes (CTLs) are critical for defence against intracellular pathogens and cancer. CTL differentiation begins when a naïve CD8+ T cell recognizes a peptide-MHC ligand complex through its T cell receptor (TCR), triggering a cascade of signalling events that drive changes in cell metabolism, growth and function. The interaction of the TCR with a particular peptide-MHC complex is exquisitely sensitive, such that single amino acid changes in the presented peptide can dramatically alter the activation of responding T cells. Multiple mechanisms have been proposed to underlie this phenomenon, but these cannot be distinguished through snapshot measurements in bulk cellular populations. It is therefore critical to measure multidimensional molecular activation events in individual cells over time. To this end, we employ multiple single-cell techniques including single-cell RNA sequencing and mass cytometry to investigate the impact of stimulation strength on naïve T cell activation. Our data show that the strength of stimulation determines the rate but not the cell-intrinsic processes of T cell activation. Such a system could allow for a finite number of rearranged TCRs and a single set of intracellular machinery to appropriately respond to a vast array of foreign stimuli.
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