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Nat Commun. 2019 Mar 4;10(1):1019. doi: 10.1038/s41467-019-08906-7.

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

Author information

1
Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, MD, 20852, USA.
2
Experimental Immunology Branch, National Cancer Institute, Bethesda, MD, 20892, USA.
3
Lymphocyte Differentiation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institute of Health, Baltimore, MD, 21224, USA.
4
Department of Immunology, Weizmann Institute of Science, 76100, Rehovot, Israel.
5
Department of Physics and Astronomy, Alfred University, 1 Saxon Drive, Alfred, NY, 14802, USA.
6
Experimental Immunology Branch, National Cancer Institute, Bethesda, MD, 20892, USA. singera@nih.gov.
7
Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, MD, 20852, USA. psun@nih.gov.

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.

PMID:
30833553
PMCID:
PMC6399321
DOI:
10.1038/s41467-019-08906-7
[Indexed for MEDLINE]
Free PMC Article

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