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

Jinghua Lu; François Van 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; Peter D. Sun

doi:10.1038/s41467-019-08906-7

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

Jinghua Lu, François Van 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, Peter D. Sun^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

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.

Original language	American English
Article number	1019
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-08906-7
State	Published - 1 Dec 2019
Externally published	Yes

Bibliographical note

Funding Information:
We thank Drs. Dinah Singer, Richard Hodes, David Garboczi and David Margulies for commenting on the manuscript. The funding of this work is provided by the Intramural Research Program (IRP) of National Cancer Institute (NCI) and National Institute of Allergy and Infectious Diseases (NIAID), and National Institute on Aging.

Publisher Copyright:
© 2019, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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Lu, J., Van Laethem, F., Bhattacharya, A., Craveiro, M., Saba, I., Chu, J., Love, N. C., Tikhonova, A., Radaev, S., Sun, X., Ko, A., Arnon, T., Shifrut, E., Friedman, N., Weng, N. P., Singer, A., & Sun, P. D. (2019). Molecular constraints on CDR3 for thymic selection of MHC-restricted TCRs from a random pre-selection repertoire. Nature Communications, 10(1), Article 1019. https://doi.org/10.1038/s41467-019-08906-7

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

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.",

author = "Jinghua Lu and {Van Laethem}, Fran{\c c}ois and Abhisek Bhattacharya and Marco Craveiro and Ingrid Saba and Jonathan Chu and Love, {Nicholas C.} and Anastasia Tikhonova and Sergei Radaev and Xiaoping Sun and Annette Ko and Tomer Arnon and Eric Shifrut and Nir Friedman and Weng, {Nan Ping} and Alfred Singer and Sun, {Peter D.}",

note = "Funding Information: We thank Drs. Dinah Singer, Richard Hodes, David Garboczi and David Margulies for commenting on the manuscript. The funding of this work is provided by the Intramural Research Program (IRP) of National Cancer Institute (NCI) and National Institute of Allergy and Infectious Diseases (NIAID), and National Institute on Aging. Publisher Copyright: {\textcopyright} 2019, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

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Lu, J, Van Laethem, F, Bhattacharya, A, Craveiro, M, Saba, I, Chu, J, Love, NC, Tikhonova, A, Radaev, S, Sun, X, Ko, A, Arnon, T, Shifrut, E, Friedman, N, Weng, NP, Singer, A & Sun, PD 2019, 'Molecular constraints on CDR3 for thymic selection of MHC-restricted TCRs from a random pre-selection repertoire', Nature Communications, vol. 10, no. 1, 1019. https://doi.org/10.1038/s41467-019-08906-7

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AU - Lu, Jinghua

AU - Van Laethem, François

AU - Bhattacharya, Abhisek

AU - Craveiro, Marco

AU - Saba, Ingrid

AU - Chu, Jonathan

AU - Love, Nicholas C.

AU - Tikhonova, Anastasia

AU - Radaev, Sergei

AU - Sun, Xiaoping

AU - Ko, Annette

AU - Arnon, Tomer

AU - Shifrut, Eric

AU - Friedman, Nir

AU - Weng, Nan Ping

AU - Singer, Alfred

AU - Sun, Peter D.

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PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

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JO - Nature Communications

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

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