MHC 限制性 TCR 从随机预选库中进行胸腺选择的 CDR3 分子限制。
Molecular constraints on CDR3 for thymic selection of MHC-restricted TCRs from a random pre-selection repertoire.
机构信息
Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, MD, 20852, USA.
Experimental Immunology Branch, National Cancer Institute, Bethesda, MD, 20892, USA.
出版信息
Nat Commun. 2019 Mar 4;10(1):1019. doi: 10.1038/s41467-019-08906-7.
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.
成熟 T 细胞上的 αβ T 细胞受体 (TCR) 库是在胸腺中选择的，但从随机产生的预选库中选择 MHC 限制性 TCR 的胸腺选择基础尚不清楚。在这里，我们对来自多个 MHC 充足和 MHC 缺乏的小鼠品系的预选和后选 TCR 进行了比较库序列分析，发现 MHC 限制性和 MHC 非依赖性 TCR 主要通过其非种系 CDR3 区域的特征来区分，许多预选 CDR3 序列与 MHC 结合不兼容。MHC 非依赖性 TCR 的胸腺选择基本上不受限制，但 MHC 特异性 TCR 的选择受到 CDR3 长度和特定氨基酸使用的限制。MHC 限制不利于 CDR3 长度超过 13 个氨基酸的 TCR，限制 CDR3β 中带正电荷和疏水性氨基酸的使用，并克隆性删除其 CDR3 肽结合区域中含有半胱氨酸的 TCR。总之，这些 MHC 施加的结构限制为将 VDJ 重组序列形成 MHC 限制性库奠定了基础。
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