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Molecular constraints on CDR3 for thymic selection of MHC-restricted TCRs from a random pre-selection repertoire

Author

Listed:
  • Jinghua Lu

    (National Institute of Allergy and Infectious Diseases)

  • François Laethem

    (National Cancer Institute)

  • Abhisek Bhattacharya

    (National Cancer Institute)

  • Marco Craveiro

    (National Cancer Institute)

  • Ingrid Saba

    (National Cancer Institute)

  • Jonathan Chu

    (National Institute of Allergy and Infectious Diseases)

  • Nicholas C. Love

    (National Cancer Institute)

  • Anastasia Tikhonova

    (National Cancer Institute)

  • Sergei Radaev

    (National Institute of Allergy and Infectious Diseases)

  • Xiaoping Sun

    (National Institute of Health)

  • Annette Ko

    (National Institute of Health)

  • Tomer Arnon

    (Weizmann Institute of Science
    Alfred University)

  • Eric Shifrut

    (Weizmann Institute of Science)

  • Nir Friedman

    (Weizmann Institute of Science)

  • Nan-Ping Weng

    (National Institute of Health)

  • Alfred Singer

    (National Cancer Institute)

  • Peter D. Sun

    (National Institute of Allergy and Infectious Diseases)

Abstract

The αβ T cell receptor (TCR) repertoire on mature T cells is selected in the thymus, but the basis for thymic selection of MHC-restricted TCRs from a randomly generated pre-selection repertoire is not known. Here we perform comparative repertoire sequence analyses of pre-selection and post-selection TCR from multiple MHC-sufficient and MHC-deficient mouse strains, and find that MHC-restricted and MHC-independent TCRs are primarily distinguished by features in their non-germline CDR3 regions, with many pre-selection CDR3 sequences not compatible with MHC-binding. Thymic selection of MHC-independent TCR is largely unconstrained, but the selection of MHC-specific TCR is restricted by both CDR3 length and specific amino acid usage. MHC-restriction disfavors TCR with CDR3 longer than 13 amino acids, limits positively charged and hydrophobic amino acids in CDR3β, and clonally deletes TCRs with cysteines in their CDR3 peptide-binding regions. Together, these MHC-imposed structural constraints form the basis to shape VDJ recombination sequences into MHC-restricted repertoires.

Suggested Citation

  • Jinghua Lu & François Laethem & Abhisek Bhattacharya & Marco Craveiro & Ingrid Saba & Jonathan Chu & Nicholas C. Love & Anastasia Tikhonova & Sergei Radaev & Xiaoping Sun & Annette Ko & Tomer Arnon & , 2019. "Molecular constraints on CDR3 for thymic selection of MHC-restricted TCRs from a random pre-selection repertoire," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08906-7
    DOI: 10.1038/s41467-019-08906-7
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    Cited by:

    1. Yafei Jiang & Jinzeng Wang & Mengxiong Sun & Dongqing Zuo & Hongsheng Wang & Jiakang Shen & Wenyan Jiang & Haoran Mu & Xiaojun Ma & Fei Yin & Jun Lin & Chongren Wang & Shuting Yu & Lu Jiang & Gang Lv , 2022. "Multi-omics analysis identifies osteosarcoma subtypes with distinct prognosis indicating stratified treatment," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Guillem Sanchez Sanchez & Maria Papadopoulou & Abdulkader Azouz & Yohannes Tafesse & Archita Mishra & Jerry K. Y. Chan & Yiping Fan & Isoline Verdebout & Silvana Porco & Frédérick Libert & Florent Gin, 2022. "Identification of distinct functional thymic programming of fetal and pediatric human γδ thymocytes via single-cell analysis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Christopher Szeto & Pirooz Zareie & Rushika C. Wirasinha & Justin B. Zhang & Andrea T. Nguyen & Alan Riboldi-Tunnicliffe & Nicole L. Gruta & Stephanie Gras & Stephen R. Daley, 2022. "Covalent TCR-peptide-MHC interactions induce T cell activation and redirect T cell fate in the thymus," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Nishant K. Singh & Jesus A. Alonso & Jason R. Devlin & Grant L. J. Keller & George I. Gray & Adarsh K. Chiranjivi & Sara G. Foote & Lauren M. Landau & Alyssa G. Arbuiso & Laura I. Weiss & Aaron M. Ros, 2022. "A class-mismatched TCR bypasses MHC restriction via an unorthodox but fully functional binding geometry," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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