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

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...

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Detalles Bibliográficos
Autores principales: Lu, Jinghua, Van Laethem, François, Bhattacharya, Abhisek, Craveiro, Marco, Saba, Ingrid, Chu, Jonathan, Love, Nicholas C., Tikhonova, Anastasia, Radaev, Sergei, Sun, Xiaoping, Ko, Annette, Arnon, Tomer, Shifrut, Eric, Friedman, Nir, Weng, Nan-Ping, Singer, Alfred, Sun, Peter D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399321/
https://www.ncbi.nlm.nih.gov/pubmed/30833553
http://dx.doi.org/10.1038/s41467-019-08906-7
Descripción
Sumario: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.