T cell receptor beta germline variability is revealed by inference from repertoire data

Area of Science:

• Immunology
• Genetics
• Bioinformatics

Background:

• Adaptive immunity relies on T and B cell receptor (TCR, BCR) repertoires.
• Adaptive immune receptor sequencing (AIRR-seq) studies immune dynamics.
• Genetic factors influencing TCR/BCR repertoires are crucial but difficult to study due to complex loci.

Purpose of the Study:

• To adapt and apply B cell AIRR-seq methods for T cell receptor (TCR) data analysis.
• To enable genotype, haplotype inference, and discovery of undocumented alleles in TCR repertoires.
• To address challenges in analyzing full and partial TCR sequence data, including gene assignment ambiguities.

Main Methods:

• Adapted a B cell pipeline for analyzing both full and partial AIRR-seq TCR data.
• Applied the pipeline for genotype and haplotype inference and discovery of undocumented alleles.
• Handled gene assignment ambiguities inherent in TCR sequence analysis.

Main Results:

• Identified 39 undocumented polymorphisms in T cell receptor Beta V (TRBV) and 31 in 5' UTR sequences.
• Confirmed a subset of findings using independent genomic approaches.
• Demonstrated that a single nucleotide polymorphism in TRBD2 alleles strongly associates with significant changes in the expressed TCR repertoire.

Conclusions:

• Revealed extensive germline variability in TCR genes.
• Showcased how a single nucleotide polymorphism can dramatically alter the entire TCR repertoire composition.
• Provided a foundation for improved TCR repertoire annotation in future research.