The molecular basis of TCR germline bias for MHC is surprisingly simple - PubMed (original) (raw)

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

K Christopher Garcia et al. Nat Immunol. 2009 Feb.

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.

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Figures

Figure 1

Figure 1

Divergence and convergence of TCR footprints on MHC molecules. (a) Interaction of VαVβ 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 Vα and Vβ 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 Vβ8 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-2Kb 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 Vα and Vβ with H-2Kb versus H-2Ld (Protein Data Bank accession numbers, 2CKB and 2OI9). H-2Kb and H-2Ld (in red) adjacent to the respective loops indicate the positions of CDR2α and CDR2β in the structures.

Figure 2

Figure 2

The ‘codon hypothesis’ for germline TCR-MHC interactions. (a) each V-gene product (where ‘Vx’ is Vα or Vβ) 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 Vα or Vβ 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.

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