Functional and biophysical characterization of an HLA-A*6801-restricted HIV-specific T cell receptor

Gostick, Emma, Cole, David ORCID: https://orcid.org/0000-0003-0028-9396, Hutchinson, Sarah L., Wooldridge, Linda, Tafuro, Sabrina, Laugel, Bruno Frederic, Lissina, A., Oxenius, Annette, Boulter, Jonathan M., Price, David ORCID: https://orcid.org/0000-0001-9416-2737 and Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135 2007. Functional and biophysical characterization of an HLA-A*6801-restricted HIV-specific T cell receptor. European Journal of Immunology 37 (2) , pp. 479-486. 10.1002/eji.200636243

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Abstract

HLA-A*6801 exhibits several unusual features. First, it is known to bind weakly to CD8 due to the presence of an A245V substitution in the α3 domain. Second, it is able to accommodate unusually long peptides as a result of peptide ‘kinking’ in the binding groove. Third, CD8+ cytotoxic T lymphocytes that recognise HLA-A*6801-restricted antigens can tolerate substantial changes in the peptide sequence without apparent loss of recognition. In addition, it has been suggested that HLA-A68-restricted TCR might bind with higher affinity than other TCR due to their selection in the presence of a decreased contribution from CD8. Here we (1) examine monoclonal T cell recognition of an HLA-A*6801-restricted HIV-1 Tat-derived 11-amino acid peptide (ITKGLGISYGR) and natural variant sequences thereof; (2) measure the affinity and kinetics of a TCR/pHLA-A68 interaction biophysically for the first time, showing that equilibrium binding occurs within the range previously determined for non-HLA-A68-restricted TCR (KD approx. 7 μM); and (3) show that “normalization” of the non-canonical HLA-A*6801 CD8-binding domain enhances recognition of agonist peptides without inducing non-specific activation. This latter effect may provide a fundamental new mechanism with which to enhance T cell immunity to specific antigens.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	HIV-1; HLA-A68; TCR.
Publisher:	John Wiley & Sons
ISSN:	0014-2980
Last Modified:	06 May 2023 02:23
URI:	https://orca.cardiff.ac.uk/id/eprint/60461

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