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

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, Eric Shifrut, Nir Friedman, Nan-Ping Weng, Alfred Singer () and Peter D. Sun ()
Additional contact information
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
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

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08906-7

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