Senior Investigator National Institutes of Health, United States
Introduction/Rationale: The αβ T cell receptors (TCR) mature in thymus to functionally recognize MHC-ligands, known as MHC-restriction. Thymic selection of T cells serves as the foundation for central tolerance and T cell immunity. Current paradigm stipulates that T cells undergo positive and negative selections through interacting with thymic expressed MHC. How MHC-restriction shapes a TCR repertoire from randomly generated pre-selection repertoire, and hence the hallmark of MHC-restricted T cell repertoire remains unclear.
Methods: T cells from various MHC-restricted animals, including B6, Balb/c and B10.BR, as well as from MHC-independent animals that are deficient in CD4, CD8 and MHC were isolated and their TCRα and β-chain sequences were obtained using next generation RNA sequencing technology.
Results: TCR repertoires from various MHC-restricted as well as MHC-independent animals were compared. The results showed that MHC-restricted and MHC-independent TCRs share similar V-gene usages but differ primarily in the composition of CDR3. Thymic selection of MHC-independent TCR is largely unconstrained, but the selection of MHC-specific TCR affects both CDR3 length and specific amino acid usage. MHC-restriction disfavors CDR3 longer than 13 amino acids, removes TCR with cysteines in their CDR3 peptide-binding regions, and limits positively charged and hydrophobic amino acids in CDR3β. Together, these attributes form the hallmarks of MHC-restricted T cell receptor repertoires.
Conclusion: MHC-expressions impose constraints to both the length and compositions of TCR repertoires.
