Human T cell receptor occurrence patterns encode immune history, genetic background, and receptor specificity

Area of Science:

• Immunology
• Genetics
• Computational Biology

Background:

• The T cell receptor (TCR) repertoire dynamically records immune exposure history and immunological memory.
• Statistical analysis of TCR repertoire sequencing data offers potential for disease association studies in large human cohorts.
• Immune responses, including TCR repertoire perturbations, are significantly influenced by the genetic background, particularly major histocompatibility complex (MHC) polymorphism.

Purpose of the Study:

• To explore the associations between major histocompatibility complex (MHC) alleles, immune exposures, and shared T cell receptors (TCRs) within a large human cohort.
• To investigate the structural basis of TCR-MHC interactions and identify sequence covariation.

Main Methods:

• Utilized a large human cohort dataset with existing repertoire sequencing data.
• Augmented the dataset with high-resolution MHC genotyping.
• Performed statistical analysis to identify patterns and associations between TCRs, MHC alleles, and immune exposures.
• Incorporated insights from solved TCR:peptide-MHC structures to guide sequence covariation analysis.

Main Results:

• Revealed significant structure within the TCR repertoire, including imprints of common pathogens.
• Identified clusters of co-occurring TCRs potentially indicating shared immune exposures.
• Demonstrated substantial variation in the strength of TCR-MHC associations across different MHC loci.
• Identified sequence covariation between TCR and MHC, guided by structural data.

Conclusions:

• The study highlights the intricate relationship between MHC genetics, immune exposures, and TCR repertoire composition.
• The findings provide a framework for understanding TCR diversity and its implications for immune memory and disease.
• Further exploration into TCR diversity and its modulation by MHC is warranted.