Abstract
αβ T cells respond to peptide epitopes presented by major histocompatibility complex (MHC) molecules. The role of T cell receptor (TCR) germline complementarity determining regions (CDR1 and 2) in MHC restriction is not well understood. Here, we examine T cell development, MHC restriction and antigen recognition where germline CDR loop structure has been modified by multiple glycine/alanine substitutions. Surprisingly, loss of germline structure increases TCR engagement with MHC ligands leading to excessive loss of immature thymocytes. MHC restriction is, however, strictly maintained. The peripheral T cell repertoire is affected similarly, exhibiting elevated cross-reactivity to foreign peptides. Our findings are consistent with germline TCR structure optimising T cell cross-reactivity and immunity by moderating engagement with MHC ligands. This strategy may operate alongside co-receptor imposed MHC restriction, freeing germline TCR structure to adopt this novel role in the TCR-MHC interface.
Highlights
Using retrogenic mice, we (i) redirected in vivo VDJ recombination to randomly diversify germline CDR structure and (ii) used chimeric T cell receptor (TCR)-βchains with γδlineage germline loops to show that the germline CDRs are not required for recognition major histocompatibility complex (MHC) ligands[9]
We conclude that the TCR repertoire of ΔβCDR1-3 mutant double positive (DP) thymocytes has enhanced affinity for self-ligands identifying an unexpected role for germline TCR structure in restraining engagement with MHC ligands
We considered that loss of germline TCR structure could promote recognition of non-MHC ligands, perhaps overriding co-receptor imposed MHC restriction and contributing to functional ligand engagement by the ΔβCDR1-3 TCR repertoire
Summary
MHC ligands and regulate peptide received: 10 February 2016 accepted: 22 September 2016. Both chimeric chains were able to direct the development of mature thymocytes and peripheral T cell compartments (Fig. 1b,c) consistent with the TCR adopting an antibody-like strategy for ligand recognition[9] These findings support the hypothesis that the CD4 and CD8 co-receptors play a key role in imprinting MHC restriction and suggest that the germline CDR regions may play a secondary role in ‘fine-tuning’ TCR engagement with MHC:peptide ligands. Germline TCR structure restrains ligand engagement during thymic T cell development To explore this idea, we produced a transgenic strain expressing a mutant TRBV16 chain in which germline structure was ‘simplified’ by introducing alanine/glycine substitutions across CDR1 and CDR2 (canonical structure group βCDR1.2/βCDR2.212) (Fig. 2a; ΔβCDR1-3). We conclude that the TCR repertoire of ΔβCDR1-3 mutant DP thymocytes has enhanced affinity for self-ligands identifying an unexpected role for germline TCR structure in restraining engagement with MHC ligands
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