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.
Highlights
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 T cell antigen receptors (TCRs) from a randomly generated pre-selection repertoire is not known
Αβ T cell antigen receptors (TCRs) normally do not recognize conformational antigenic epitopes but instead are selected in the thymus to recognize linear antigenic peptides bound to major histocompatibility complexes[2], a feature known as MHC-restriction
This study identifies molecular constraints that are primarily imposed on hyper-variable TCR-CDR3 segments during thymic selection of MHC-restricted TCR repertoires
Summary
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. Αβ T cell antigen receptors (TCRs) normally do not recognize conformational antigenic epitopes but instead are selected in the thymus to recognize linear antigenic peptides bound to major histocompatibility complexes (pMHC)[2], a feature known as MHC-restriction. Because CD4/CD8 coreceptors only bind to MHC molecules, thymic selection in wildtype mice generates only MHCr TCR repertoires that recognize linear antigenic peptides presented by MHC. Genetic deletion of both CD4 and CD8 coreceptor proteins in developing thymocytes makes Lck available to all TCRs, which can signal thymic selection upon engagement of any intra-thymic ligand. Thymic selection in mice genetically deficient in both co-receptor proteins and MHC (B2m−/−H-2Ab1−/−CD4−/−CD8a−/− mice, referred to as Quad-deficient mice) generates MHC-independent (MHCi) TCRs that resemble antibodies in recognizing native conformational antigenic epitopes independently of MHC5–8
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