Measures of epitope binding degeneracy from T cell receptor repertoires

Adaptive immunity is driven by specific binding of hyper-variable receptors to diverse molecular targets. The sequence diversity of receptors and targets are both individually known but, because multiple receptors can recognize the same target, a measure of the effective 'functional' diver...

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Bibliographic Details
Published in:bioRxiv
Main Authors: Mayer, Andreas, Callan, Curtis G
Format: Paper
Language:English
Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 15.11.2022
Cold Spring Harbor Laboratory
Edition:1.2
Subjects:
Adaptive immunity
Amino acid sequence
Antigens
Epitopes
Immune system
Immunology
Lymphocytes T
Statistical analysis
T cell receptors
repertoire sequencing
specificity
receptor-ligand binding
T cells
ISSN:2692-8205, 2692-8205
Online Access:Get full text
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Summary:Adaptive immunity is driven by specific binding of hyper-variable receptors to diverse molecular targets. The sequence diversity of receptors and targets are both individually known but, because multiple receptors can recognize the same target, a measure of the effective 'functional' diversity of the human immune system has remained elusive. Here, we show that sequence near-coincidences within T cell receptors that bind specific epitopes provide a new window into this problem, and allow the quantification of how binding probability co-varies with sequence. We find that near-coincidence statistics within epitope-specific repertoires imply a measure of binding degeneracy to amino acid changes in receptor sequence that is consistent across disparate experiments. Paired data on both chains of the heterodimeric receptor are particularly revealing since simultaneous near-coincidences are rare and we show how they can be exploited to estimate the number of epitope responses that created the memory compartment. In addition, we find that paired-chain coincidences are strongly suppressed across donors with different human leukocyte antigens, evidence for a central role of antigen-driven selection in making paired chain receptors public. These results demonstrate the power of coincidence analysis to reveal the sequence determinants of epitope binding in receptor repertoires.Competing Interest StatementThe authors have declared no competing interest.Footnotes* The text has been revised to give additional intuition and to increase clarity.
Bibliography:SourceType-Working Papers-1
ObjectType-Working Paper/Pre-Print-1
content type line 50
Competing Interest Statement: The authors have declared no competing interest.
ISSN:2692-8205
2692-8205
DOI:10.1101/2022.07.25.501373