Using a ‘reductionist’ system with limited and stable components, Abu-Shah and Trendel et al. demonstrated that human T cell TCRs respond to peptide:MHC antigen (Ag) and produce different cytokines at a comparable Ag concentration for all cytokines, implying a single Ag threshold (defined by Ag affinity) for TCR triggering of different cytokine responses. A similar result was observed for cytokine production and cell killing by memory T cells. Addition of costimulatory ligands (CD28, CD58, or CD70) enhanced cytokine production and, in some cases (especially CD58), reduced the absolute threshold, but not differentially among cytokines.
Contributed by Ed Fritsch
ABSTRACT: T cells recognizing cognate pMHC Ags 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 hypothesized to exhibit different Ag dose and affinity thresholds, suggesting that pathogen-specific information may be encoded within the nature of the Ag. In this study, using systematic experiments in a reductionist system, in which primary human CD8(+) T cell blasts are stimulated by recombinant peptides presented on MHC Ag alone, we show that different inflammatory cytokines have comparable Ag dose thresholds across a 25,000-fold variation in affinity. Although costimulation by CD28, CD2, and CD27 increased cytokine production in this system, the Ag threshold remained comparable across different cytokines. When using primary human memory CD8(+) T cells responding to autologous APCs, equivalent thresholds were also observed for different cytokines and killing. These findings imply a simple phenotypic model of TCR signaling in which multiple T cell responses share a common rate-limiting threshold and a conceptually simple model of CD8(+) T cell Ag recognition, in which Ag dose and affinity do not provide any additional response-specific information.