The molecular basis of TCR germline bias for MHC is surprisingly simple

Abstract

The elusive etiology of germline bias of the T cell receptor (TCR) for major histocompatibility complex (MHC) has been clarified by recent 'proof-of-concept' structural results demonstrating the conservation of specific TCR-MHC interfacial contacts in complexes bearing common variable segments and MHC allotypes. We suggest that each TCR variable-region gene product engages each type of MHC through a 'menu' of structurally coded recognition motifs that have arisen through coevolution. The requirement for MHC-restricted T cell recognition during thymic selection and peripheral surveillance has necessitated the existence of such a coded recognition system. Given these findings, a reconsideration of the TCR-peptide-MHC structural database shows that not only have the answers been there all along but also they were predictable by the first principles of physical chemistry.

Figure 1

Divergence and convergence of TCR footprints on MHC molecules. (a) Interaction of V_αV_β with peptide-MHC, viewed down the MHC groove (Protein Data Bank accession number, 2CKB). (b) ’Footprint‘ view of a showing the stereotyped polarity of the V_α and V_β CDR loops on pMHC. (c) Convergent footprint polarity but diverse CDR loop positions in nine different TCR-pMHC complexes (Protein Data Bank accession numbers, 1AO7, 1FO0, 1J8H, 1KJ2, 1ZG1, 2NX5, 1MI5, 1OGA and 1U3H). (d) Close superpositions (in circle) of the contacts of V_β8 CDR1 and CDR2 with the I-A MHC α1 helix in six different TCR-pMHC complexes (Protein Data Bank accession numbers, 1U3H, 2Z31, 2PXY, 1D9K, 3C60 and 3C61). (e) Retention of similar germline-mediated contacts by the BM3.3 TCR with H-2K^b in three different peptide complexes (Protein Data Bank accession numbers, 1FO0, 2OL3 and 1NAM). (f) Use of alternative ‘codons’ for interaction of the 2C TCR V_α and V_β with H-2K^b versus H-2L^d (Protein Data Bank accession numbers, 2CKB and 2OI9). H-2K^b and H-2L^d (in red) adjacent to the respective loops indicate the positions of CDR2α and CDR2β in the structures.

Figure 2

The ‘codon hypothesis’ for germline TCR-MHC interactions. (a) each V-gene product (where ‘V_x’ is V_α or V_β) interacts with diverse MHC surface residues on the tops of the helices of different MHC molecules (Y, X and Z) by distinct yet specific mechanisms. That is, each CDR1 and/or CDR2 engages different MHC surfaces in diverse ways: the pairwise interactions that form each codon need not be shared by different MHC molecules. The CDR-MHC interface is presented as ‘teeth’ on the respective interacting surfaces. The same ‘teeth’ in a particular V_α or V_β CDR1-CDR2 engage different MHC surface structures (opposing ‘teeth’) in each complex in unique, highly specific ways. (b) An individual TCR germline V segment can engage one MHC molecule using several distinct codons (A, B and C) that are influenced by the interactions of CDR3 with the MHC-bound peptide. This is presented here as different docking geometries (‘footprints’) on the MHC that are mediated by the interaction of common residues on the TCR CDR1-CDR2 with different ‘registers’ of the MHC helix in each peptide complex. Inset, free energy diagram indicating that each footprint represents a low-energy binding solution (‘click’) rather than an energetic continuum.