Minimal conformational plasticity enables TCR cross-reactivity to different MHC class II heterodimers

Scientific Reports (Impact Factor: 5.58). 09/2012; 2:629. DOI: 10.1038/srep00629
Source: PubMed


Successful immunity requires that a limited pool of αβ T-cell receptors (TCRs) provide cover for a vast number of potential foreign peptide antigens presented by 'self' major histocompatibility complex (pMHC) molecules. Structures of unligated and ligated MHC class-I-restricted TCRs with different ligands, supplemented with biophysical analyses, have revealed a number of important mechanisms that govern TCR mediated antigen recognition. HA1.7 TCR binding to the influenza hemagglutinin antigen (HA(306-318)) presented by HLA-DR1 or HLA-DR4 represents an ideal system for interrogating pMHC-II antigen recognition. Accordingly, we solved the structure of the unligated HA1.7 TCR and compared it to both complex structures. Despite a relatively rigid binding mode, HA1.7 T-cells could tolerate mutations in key contact residues within the peptide epitope. Thermodynamic analysis revealed that limited plasticity and extreme favorable entropy underpinned the ability of the HA1.7 T-cell clone to cross-react with HA(306-318) presented by multiple MHC-II alleles.

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Available from: Pierre Rizkallah, Oct 09, 2015
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    • "Further hindrance in defining overall molecular aspects of ADR arise from lack of a direct understanding of TCR mechanics in the entire process. Currently conflicting results exist on what constitutes differences between signaling and non-signaling TCR based on structural studies [4,32,36,39,56]. Related to ADR or autoimmune disease, these have focused on the pHLA interactions themselves, and largely neglected TCR conformations, primarily as HLA types vary between individuals, while TCR subtypes do not [1,10,14]. "
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    • "The crystallographic R/Rfree factors were 23.4 and 29.5%, consistent with the expected ratio range (Tickle et al., 2000). In many cases, although not all (Borbulevych et al., 2011b; Holland et al., 2012), TCR CDR loops have been shown to undergo numerous, and sometimes large, conformational changes upon pMHC binding (Armstrong et al., 2008b). Superposition of the free and the bound A6c134 TCR showed that, although the overall conformation of the TCR was virtually identical (Figure 2A), the CDR loops underwent substantial movements (Figure 2B). "
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