Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

Abstract

T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose–response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways.

Comparison of T Cell Activities Mediated by Human TCRs and CARs That Use the Same Recognition Domains

“…We also noted that peptide titrations, representing increasing antigen densities, often yielded bell-shaped curves as observed in studies with TCRs (42) and CARs (45). The bell-shaped curves were in general seen with both TCRs and CARs, as long as the later were able to be titrated at sufficiently high peptide concentrations beyond the peak cytokine levels.…”

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

“…To investigate the antigen threshold required to elicit different effector cytokines, we first utilised a reductionist system to exclude any contribution from extrinsic factors such as pMHC stability and variation in co-stimulatory ligands on APCs. In this system, primary human CD8 + T cell blasts that have been transduced to express the affinity enhanced 1G4 TCR (c58c61) (13,14) were stimulated by plate-immobilised recombinant pMHC (15)(16)(17)(18). The use of the c58c61 TCR allowed us to explore cytokine thresholds when T cells are stimulated by a panel of 8 pMHCs that span >10-million fold variation in affinity from supra-physiological therapeutic affinities (pM) to physiological affinities (µM) ( Fig.…”

Using the force to find the peptides you’re looking for

“…They use this data to argue against the serial triggering hypothesis (14), which posits that a single pMHC can sequentially trigger multiple TCRs. This is indeed a very intriguing and provocative experiment, and more work will be required to square their conclusion with the evidence supporting serial triggering (15), including why high-affinity pMHC interactions can sometimes paradoxically drive decreased downstream cell activation (16).…”