Human CD8+ T Cells Exhibit a Shared Antigen Threshold for Different Effector Responses

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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. Key Points CD8+ T cells produce TNF-α, IL-2, and IFN-γ with similar Ag thresholds. Costimulation decreases Ag thresholds similarly for different cytokines. A common rate-limiting switch downstream of the TCR can explain these findings.
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Funding Information
  • UCB
  • Engineering and Physical Sciences Research Council
  • Konrad Adenauer Stiftung
  • Edward Penley Abraham Trust
  • Cellular Immunology Unit Trust
  • Wellcome Trust (203737/Z/16/Z, 100262Z/12/Z, 207537/Z/17/Z)

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