Abstract
The crystal structures of unliganded and liganded pMHC molecules provide a structural basis for TCR recognition yet they represent ‘snapshots’ and offer limited insight into dynamics that may be important for interaction and T cell activation. MHC molecules HLA-B*3501 and HLA-B*3508 both bind a 13 mer viral peptide (LPEP) yet only HLA-B*3508-LPEP induces a CTL response characterised by the dominant TCR clonetype SB27. HLA-B*3508-LPEP forms a tight and long-lived complex with SB27, but the relatively weak interaction between HLA-B*3501-LPEP and SB27 fails to trigger an immune response. HLA-B*3501 and HLA-B*3508 differ by only one amino acid (L/R156) located on α2-helix, but this does not alter the MHC or peptide structure nor does this polymorphic residue interact with the peptide or SB27. In the absence of a structural rationalisation for the differences in TCR engagement we performed a molecular dynamics study of both pMHC complexes and HLA-B*3508-LPEP in complex with SB27. This reveals that the high flexibility of the peptide in HLA-B*3501 compared to HLA-B*3508, which was not apparent in the crystal structure alone, may have an under-appreciated role in SB27 recognition. The TCR pivots atop peptide residues 6–9 and makes transient MHC contacts that extend those observed in the crystal structure. Thus MD offers an insight into ‘scanning’ mechanism of SB27 that extends the role of the germline encoded CDR2α and CDR2β loops. Our data are consistent with the vast body of experimental observations for the pMHC-LPEP-SB27 interaction and provide additional insights not accessible using crystallography.
Highlights
Introduction abT cell receptors (TCR) expressed on the surface of CD8+ T cells generally recognise specific antigenic or aberrant peptide fragments that are bound to a cell surface major histocompatibility complex (MHC) class I molecule
When pathogens replicate within a host cell, their proteins are degraded into peptides, which are captured by the major histocompatibility complex (MHC) and brought to the cell surface
We ask how TCRs discriminate between structurally similar pMHCs? We address this by focusing on two MHC molecules that differ by a single change, both bind the same peptide but only one instigates a dominant immune response
Summary
T cell receptors (TCR) expressed on the surface of CD8+ T cells generally recognise specific antigenic or aberrant peptide fragments (usually 8–10 mers) that are bound to a cell surface MHC class I molecule. This interaction is central to adaptive T cell mediated immunity and induces signalling that results in T cell proliferation and differentiation into effector and memory T cells [1]. The Va and Vb chains of the TCR sit atop the amino- (N-) and carboxy (C-) terminal residues of the peptide respectively (Figure 1B) In this conserved binding orientation the hypervariable CDR3 loops contact the peptide, whereas the germline-encoded CDR1 and CDR2 loops contact the MHC helices [3]. It is likely that evolutionarily conserved interactions between certain amino acids in the CDR1 and CDR2 loops and the MHC backbone govern the conserved binding orientation of the TCR atop the MHC, allowing some flexibility in the binding angle and exact positioning of the TCR [4,5,6,7,8]
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