TY - JOUR
T1 - Molecular constraints on CDR3 for thymic selection of MHC-restricted TCRs from a random pre-selection repertoire
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.
N1 - Publisher Copyright: © 2019, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85062382615&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-019-08906-7
DO - https://doi.org/10.1038/s41467-019-08906-7
M3 - مقالة
C2 - 30833553
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1019
ER -