Journal Article

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

Arnon, Tomer, Ko, Annette, Love, Nicholas C., Tikhonova, Anastasia, Bhattacharya, Abhisek, Chu, Jonathan, Lu, Jinghua, Van Laethem, François, Craveiro, Marco, Sun, Peter D., Friedman, Nir, Saba, Ingrid, Sun, Xiaoping, Weng, Nan-Ping, Singer, Alfred, Radaev, Sergei, Shifrut, Eric

2019

Overview

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. For T cells, functional antigen receptors are selected in the thymus from a pre-selection repertoire by interaction with self MHCs. Here the authors show that specific, non-germline coded features located in the complementarity determining region 3 of the pre-selection antigen receptors are essential for the selection of MHC-restricted repertoire.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/91 / 45 / 631/250/1619/554/1775 / 631/250/21/324 / 631/250/2152/2496 / 631/250/2152/2497 / Amino Acid Sequence / Amino acids / Animals / Binding / Complementarity Determining Regions - chemistry / Complementarity Determining Regions - genetics / Complementarity Determining Regions - immunology / Complementarity-determining region 3 / Humanities and Social Sciences / Hydrophobicity / Lymphocyte Activation / Lymphocytes / Lymphocytes T / Major histocompatibility complex / Major Histocompatibility Complex - genetics / Major Histocompatibility Complex - immunology / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Mice, Knockout / multidisciplinary / Receptors, Antigen, T-Cell - chemistry / Receptors, Antigen, T-Cell - genetics / Receptors, Antigen, T-Cell - immunology / Science / Science (multidisciplinary) / Sequence Analysis, Protein / T cell receptors / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / Thymus / Thymus Gland - immunology / V(D)J Recombination