T cell cytolytic capacity is independent of initial stimulation strength

Abstract

How cells respond to myriad stimuli with finite signaling machinery is central to immunology. In naive T cells, the inherent effect of ligand strength on activation pathways and endpoints has remained controversial, confounded by environmental fluctuations and intercellular variability within populations. Here we studied how ligand potency affected the activation of CD8 T cells in vitro, through the use of genome-wide RNA, multi-dimensional protein and functional measurements in single cells. Our data revealed that strong ligands drove more efficient and uniform activation than did weak ligands, but all activated cells were fully cytolytic. Notably, activation followed the same transcriptional pathways regardless of ligand potency. Thus, stimulation strength did not intrinsically dictate the T cell-activation route or phenotype; instead, it controlled how rapidly and simultaneously the cells initiated activation, allowing limited machinery to elicit wide-ranging responses.

Human CD8+T cells exhibit a shared antigen threshold for different effector responses

“…In this model, pathogen-specific information may be encoded by TCR-extrinsic factors, such as ligands to other co-signalling receptors (42). This is consistent with recent in-vitro (43) and in-vivo (44) data showing that different antigen doses and affinities produce CD8 + T cells with similar response potentials. This conclusion may differ for CD4 + T cell differentiation, where antigen dose can selectively induce regulatory T cells, Th1, and Th2 phenotypes (45)(46)(47).…”

Two signal half‐century: From negative selection of self‐reactivity to positive selection of near‐self‐reactivity

“…At half‐optimum lectin concentrations, there is a quantal, all‐or‐none response (ie, all the cells do not half‐respond) . This is now observed with specific antigen‐stimulated cells . It is now known that certain lectins are specific for T cells, which have protein receptors (TCRs) with uniform glycan attachments that lectins can bind; hence T cell responsiveness to lectins is polyclonal .…”

“…9,10 This is now observed with specific antigenstimulated cells. 11,12 It is now known that certain lectins are specific for T cells, which have protein receptors (TCRs) with uniform glycan attachments that lectins can bind; hence T cell responsiveness to lectins is polyclonal. 13,14 Shortly after lectin binding, as with specific antigen-activated T cells 11 there is increased transcription of mRNAs encoding distinctive proteins (eg, chemokine CCL3 and transcription factors EGR1, Fos and FosB).…”

“…11,12 It is now known that certain lectins are specific for T cells, which have protein receptors (TCRs) with uniform glycan attachments that lectins can bind; hence T cell responsiveness to lectins is polyclonal. 13,14 Shortly after lectin binding, as with specific antigen-activated T cells 11 there is increased transcription of mRNAs encoding distinctive proteins (eg, chemokine CCL3 and transcription factors EGR1, Fos and FosB). [15][16][17] Of singular interest was the finding that concanavalin-A (Con-A), a mannan-binding lectin (MBL) from jack bean, would at low concentrations activate T cells and at high concentrations harness complement to destroy them.…”

Quantitative analysis of how Myc controls T cell proteomes and metabolic pathways during T cell activation

“…To explore the mechanism for Myc control of amino acid transport in activated T cells we examined the relationship between Myc and amino acid transporter mRNA expression. Single cell RNAseq analysis of antigen activated OT1 CD8 + T cells (Richard et al, 2018) shows a strong correlation at the single cell level of Myc mRNA expression and expression of mRNA for Slc7a5, Slc7a1 and Slc1a5 ( Fig 4A). Expression of Myc mRNA clearly precedes increased expression of mRNA for Slc7a5 and Slc1a5 ( Fig 4A).…”