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

Abstract

T cells recognising cognate pMHC antigens become activated to elicit a myriad of cellular responses, such as target cell killing and the secretion of different cytokines, that collectively contribute to adaptive immunity. These effector responses have been hypothesised to exhibit different antigen dose and affinity thresholds, suggesting that pathogen-specific information may be encoded within the nature of the antigen. Here, using systematic experiments in a reductionist system, where primary human CD8 + T cell blasts are stimulated by recombinant pMHC antigen alone, we show that different inflammatory cytokines have comparable antigen dose thresholds across a 25,000-fold variation in affinity. Although co-stimulation by CD28, CD2, and CD27 increased cytokine production in this system, the antigen threshold remained comparable across different cytokines. When using primary human memory CD8 + T cells responding to autologous antigen presenting cells equivalent thresholds were also observed for cytokine production and killing. These findings imply a simple phenotypic model of TCR signalling where multiple T cell responses share a common rate-limiting threshold and a conceptually simple model of antigen recognition, where the chance factor of antigen dose and affinity do not provide any additional response-specific information.

T cells exhibit unexpectedly low discriminatory power and can respond to ultra-low affinity peptide-MHC ligands

“…We hypothesised that the absence of ligands for co-signalling receptors may account for this reduction in antigen discrimination. It has been shown that ligation of co-signalling receptors can greatly enhance antigen potency (42,44). Inclusion of recombinant ICAM1 (a ligand of LFA-1) or CD58 (the ligand to CD2) increased TCR downregulation ( Figure S4) and antigen potency ( Figure 3C) in this experimental system, consistent with previous reports using APCs (44,45).…”

“…Since APCs express ligands for many co-signalling receptors, we adopted a reductionist system (42,43) where recombinant pMHCs are presented on plates with or without ligands for co-signalling receptors before being used as stimulation surfaces for 1G4 T cell blasts ( Figure 3A).…”

The discriminatory power of the T cell receptor

“…4D). This is consistent with a TCR-proximal mechanism of antigen discrimination (44,45) that has a similar threshold for different T cell responses (46)(47)(48).…”

“…We found a number of studies, including previous work from our laboratory, that relied on reductionist systems where recombinant pMHC is presented in isolation on plates (e.g. biotinylated pMHC immobilised on streptavidin-coated plates (10,11,47,53,54)). To assess the impact of artificial presentation, we quantified discrimination powers from these studies finding that α decreased significantly from 2.0 on APCs to 0.93 when presented on artificial surfaces (Fig.…”

Predicting Cross-Reactivity and Antigen Specificity of T Cell Receptors

“…There is accumulating evidence that genetic background, private TCR specificities and immunological history are key factors contributing to the final outcome of antigen exposure-whether to confer protective immunity or induce damaging immunopathology (25,38,39). It is of note that peptide recognition is not a simple on/off event, and that the same T cell can respond in different ways to modified peptides, by for example, pMHC affinity and dose thresholds (40,41), co-stimulatory molecules (42), and hierarchical organization of thresholds (43,44).…”