Population variability in the generation and thymic selection of T-cell repertoires

The diversity of T-cell receptor (TCR) repertoires is achieved by a combination of two intrinsically stochastic steps: random receptor generation by VDJ recombination, and selection based on the recognition of random self-peptides presented on the major histocompatibility complex. These processes lead to a large receptor variability within and between individuals. However, the characterization of the variability is hampered by the limited size of the sampled repertoires. We introduce a new software tool SONIA to facilitate inference of individual-specific computational models for the generation and selection of the TCR beta chain (TRB) from sequenced repertoires of 651 individuals, separating and quantifying the variability of the two processes of generation and selection in the population. We find not only that most of the variability is driven by the VDJ generation process, but there is a large degree of consistency between individuals with the inter-individual variance of repertoires being about ~2% of the intra-individual variance. Known viral-specific TCRs follow the same generation and selection statistics as all TCRs.

[1]  C. Benoist,et al.  Regulation of N-region diversity in antigen receptors through thymocyte differentiation and thymus ontogeny. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[2]  J. Crawford,et al.  Selected before selection: A case for inherent antigen bias in the T cell receptor repertoire. , 2019, Current opinion in systems biology.

[3]  M. Lieber,et al.  The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. , 2010, Annual review of biochemistry.

[4]  William S. DeWitt,et al.  Immunosequencing identifies signatures of cytomegalovirus exposure history and HLA-mediated effects on the T cell repertoire , 2017, Nature Genetics.

[5]  P. Bradley,et al.  Quantifiable predictive features define epitope-specific T cell receptor repertoires , 2017, Nature.

[6]  Alessandro Sette,et al.  Identifying specificity groups in the T cell receptor repertoire , 2017, Nature.

[7]  Quentin Marcou,et al.  High-throughput immune repertoire analysis with IGoR , 2017, Nature Communications.

[8]  Robert A Holt,et al.  Sequence analysis of T-cell repertoires in health and disease , 2013, Genome Medicine.

[9]  D. Schatz,et al.  V(D)J recombination: mechanisms of initiation. , 2011, Annual review of genetics.

[10]  Thierry Mora,et al.  The Past, Present, and Future of Immune Repertoire Biology – The Rise of Next-Generation Repertoire Analysis , 2013, Front. Immunol..

[11]  Yun S. Song,et al.  Estimating Copy Number and Allelic Variation at the Immunoglobulin Heavy Chain Locus Using Short Reads , 2016, PLoS Comput. Biol..

[12]  I. Springer,et al.  Prediction of Specific TCR-Peptide Binding From Large Dictionaries of TCR-Peptide Pairs , 2019, bioRxiv.

[13]  Timothy K Starr,et al.  Positive and negative selection of T cells. , 2003, Annual review of immunology.

[14]  Markus Heinonen,et al.  Determining epitope specificity of T cell receptors with TCRGP , 2019, bioRxiv.

[15]  John Shawe-Taylor,et al.  Tracking global changes induced in the CD4 T-cell receptor repertoire by immunization with a complex antigen using short stretches of CDR3 protein sequence , 2014, bioRxiv.

[16]  Yuval Elhanati,et al.  Predicting the spectrum of TCR repertoire sharing with a data‐driven model of recombination , 2018, bioRxiv.

[17]  Thierry Mora,et al.  Precise tracking of vaccine-responding T cell clones reveals convergent and personalized response in identical twins , 2018, Proceedings of the National Academy of Sciences.

[18]  Thierry Mora,et al.  Statistical inference of the generation probability of T-cell receptors from sequence repertoires , 2012, Proceedings of the National Academy of Sciences.

[19]  Benjamin Chain,et al.  High-throughput sequencing of the T-cell receptor repertoire: pitfalls and opportunities , 2017, Briefings Bioinform..

[20]  William S. DeWitt,et al.  Human T cell receptor occurrence patterns encode immune history, genetic background, and receptor specificity , 2018, bioRxiv.

[21]  Daniel C. Douek,et al.  Sharing of T cell receptors in antigen-specific responses is driven by convergent recombination , 2006, Proceedings of the National Academy of Sciences.

[22]  P. Marrack,et al.  Molecules in medicine mini review: the αβ T cell receptor , 2014, Journal of Molecular Medicine.

[23]  P. Greenberg,et al.  Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities. , 2007, Blood.

[24]  S. Tonegawa,et al.  Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Philip J. R. Goulder,et al.  Phenotypic Analysis of Antigen-Specific T Lymphocytes , 1996, Science.

[26]  Jared Gartner,et al.  Tumor- and Neoantigen-Reactive T-cell Receptors Can Be Identified Based on Their Frequency in Fresh Tumor , 2016, Cancer Immunology Research.

[27]  Yuval Elhanati,et al.  OLGA: fast computation of generation probabilities of B- and T-cell receptor amino acid sequences and motifs , 2018, bioRxiv.

[28]  L. Klein,et al.  A central role for central tolerance. , 2006, Annual review of immunology.

[29]  C. Janeway.  Immunobiology: The Immune System in Health and Disease , 1996 .

[30]  D. Pardoll,et al.  DeepTCR: a deep learning framework for revealing structural concepts within TCR Repertoire , 2018, bioRxiv.

[31]  M. Nielsen,et al.  NetTCR: sequence-based prediction of TCR binding to peptide-MHC complexes using convolutional neural networks , 2018, bioRxiv.

[32]  P. Lindau,et al.  Advances and applications of immune receptor sequencing in systems immunology , 2017 .

[33]  Yuval Elhanati,et al.  Quantifying selection in immune receptor repertoires , 2014, Proceedings of the National Academy of Sciences.

[34]  IGoR: a tool for high-throughput immune repertoire analysis , 2017, 1705.08246.

[35]  Andrew K. Sewell,et al.  VDJdb in 2019: database extension, new analysis infrastructure and a T-cell receptor motif compendium , 2019, Nucleic Acids Res..