T cells exhibit unexpectedly low discriminatory power and can respond to ultra-low affinity peptide-MHC ligands
Pettmann, J.; Abu-Shah, E.; Kutuzov, M.; Wilson, D. B.; Dustin, M.; Davis, S.; van der Merwe, P. A.; Dushek, O.
10.1101/2020.11.14.382630 bioRxivShow abstract
T cells use their T cell receptors (TCRs) to discriminate between peptide MHC (pMHC) ligands that bind with different affinities but precisely how different remains controversial. This is partly because the affinities of physiologically relevant interactions are often too weak to measure. Here, we introduce a surface plasmon resonance protocol to measure ultra-low TCR/pMHC affinities (KD ~ 1000 M). Using naive, memory, and blasted human CD8+ T cells we find that their discrimination power is unexpectedly low, in that they require a large >100-fold decrease in affinity to abolish responses. Interestingly, the discrimination power reduces further when antigen is presented in isolation on artificial surfaces but can be partially restored by adding ligands to CD2 or LFA-1. We were able to fit the kinetic proof-reading model to our data, yielding the first estimates for both the time delay (2.8 s) and number of biochemical steps (2.67). The fractional number of steps suggest that one of the proof-reading steps is not easily reversible.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- The discriminatory power of the T cell receptor 99%
- A B cell actomyosin arc network couples integrin co-stimulation to mechanical force-dependent immune synapse formation 96%
- Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses in autoimmune disorders 95%
Similar papers in this journal
- Inefficient exploitation of accessory receptors reduces the sensitivity of chimeric antigen receptors. 98%
- Differential Roles of Kinetic On- and Off-Rates in T-Cell Receptor Signal Integration Revealed with a Modified Fab'-DNA Ligand 97%
- MEK inhibition enhances presentation of targetable MHC-I tumor antigens in mutant melanomas 96%
Similar papers in this journal
Similar papers in this journal
- Affinity-engineered human antibodies detect celiac disease gluten pMHC complexes and inhibit T-cell activation 96%
- Innate receptors with high specificity for HLA class I-peptide complexes 95%
- Quality of vaccination-induced T cell responses is conveyed by polyclonality and high, but not maximum, antigen receptor avidity 95%
Similar papers in this journal
- TET2 regulates early and late transitions in exhausted CD8+ T-cell differentiation and limits CAR T-cell function 95%
- Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector activities 95%
- When killers become thieves: trogocytosed PD-1 inhibits NK cells in cancer 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.