Combining genotypes and T cell receptor distributions to infer genetic loci determining V(D)J recombination probabilities
Year: 2022
Type: article
Abstract: Every T cell receptor (TCR) repertoire is shaped by a complex probabilistic tangle of genetically determined biases and immune exposures. T cells combine a random V(D)J recombination process with a selection process to generate highly diverse and functional TCRs. The extent to which an individual’s genetic background is associated with their resulting TCR repertoire diversity has yet to be fully explored. Using a previously published repertoire sequencing dataset paired with high-resolution genome-wide genotyping from a large human cohort, we infer specific genetic loci associated with V(D)J recombination probabilities using genome-wide association inference. We show that V(D)J gene usage profiles are associated with variation in the TCRB locus and, specifically for the functional TCR repertoire, variation in the major histocompatibility complex locus. Further, we identify specific variations in the genes encoding the Artemis protein and the TdT protein to be associated with biasing junctional nucleotide deletion and N-insertion, respectively. These results refine our understanding of genetically-determined TCR repertoire biases by confirming and extending previous studies on the genetic determinants of V(D)J gene usage and providing the first examples of trans genetic variants which are associated with modifying junctional diversity. Together, these insights lay the groundwork for further explorations into how immune responses vary between individuals.
Source: eLife
DOI: 10.7554/elife.73475
Authors: Magdalena L Russell, Aisha Souquette, David M Levine, Stefan A Schattgen, E Kaitlynn Allen, Guillermina Kuan, Noah Simon, Angel Balmaseda, Aubree Gordon, Paul G Thomas, Frederick A Matsen, Philip Bradley
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: G151485645, Genetic Analysis of Airflow Obstruction After Stem Cell Transplantation, Biomarker Discovery in Chronic Graft-vs-Host Disease, High-Performance Compute Cluster for Comprehensive Cancer and Infectious Diseases Research, Genetic epidemiology of TLR4 alleles and bacteremia, Whole Genome Association Analysis of Hematopoietic Cell Transplant Outcome, G2395463226, G273506865, Immunobiology of Tolerance FF Allogeneic Hematopoietic Cell Transplantation, G4266498966, G4431735618, G5728891395, Whole Genome Association Analysis of Hematopoietic Cell Transplant (HCT) Outcome, G7314510119, Mechanisms to diversify repertoire and modify T cell activity after infection, Blending deep learning with probabilistic mechanistic models to predict and understand the evolution and function of adaptive immune receptors, Dynamics of Influenza Transmission in Nicaraguan Households, Decoding the interactions between T cell receptors and peptide-MHC, Cancer Center Support Grant, G918065593, G921956316
OpenAlex ID: W4225810652