Structural alterations in peptide-MHC recognition by self-reactive T cell receptors

Abstract

The crystal structures of five autoimmune T cell receptor (TCR)-peptide-MHC complexes reveal substantial structural alterations compared to antimicrobial TCRs. The two human TCRs bind their self-peptide-MHC ligands with an altered topology, while the three mouse receptors recognize a self-peptide that only partially fills the MHC-binding groove. In most cases the peptide is contacted only by a subset of available TCR complementarity-determining loops and there is a paucity of hydrogen bonds from TCR to peptide. These suboptimal binding properties may have enabled escape from negative thymic selection. While only minute amounts of antigen are typically available for negative selection, the antigens recognized by many autoimmune TCRs are abundant in the target organ. Such compensatory mechanisms can allow self-reactive T cells with altered TCR-binding properties to be pathogenic.

Figure 1

Structural comparison of TCR–peptide–MHC class II complexes. (a) Upper panel: Top view of the human anti-microbial HA1.7–HA–DR1 complex (PDB accession code 1FYT). MHC α-chain is dark blue and β-chain is light blue; TCR α-chain is magenta and β-chain is yellow; peptide is an orange line. The peptide residue occupying the P5 position of the peptide-binding grove is shown as an orange sphere. Bottom panel: Positions of the Vαand VβCDR loops (numbered 1–3) on the peptide–MHC surface. (b) The human autoimmune Ob.1A12–MBP–DR2b complex (1YMM). (c) The human autoimmune 3A6–MBP–DR2a complex (1ZGL). (d) The human anti-tumor E8–mutTPI–DR1 complex (2IAM). (e) The mouse autoimmune 172.10–MBP–I-A^u complex (1U3H). The comparison shows the shift of human self-reactive TCRs Ob.1A12, 3A6 and E8 towards the peptide N-terminus and the MHC class II β chain helix (light blue).

Figure 2

Position of TCR CDR3 loops over foreign, self, or mutant self-peptide antigens in TCR–peptide–MHC class II complexes. Color codes for TCR, MHC and peptide are the same as in Figure 1. The peptide is drawn in ball-and-stick representation with carbon atoms in orange, oxygen atoms in red, and nitrogen atoms in blue. The residue located in the center of the pocket formed by the CDR3αand CDR3βloops is labeled. (a) The human anti-microbial HA1.7–HA–DR1 complex. (b) The human autoimmune Ob.1A12–MBP–DR2b complex. (c) The human autoimmune 3A6–MBP–DR2a complex. (d) The human anti-tumor E8–mutTPI–DR1 complex. (e) The mouse autoimmune 172.10–MBP–I-A^u complex. TCRs 1934.4 and cl19 dock very similarly.