The molecular basis of T cell receptor recognition of citrullinated tenascin-C presented by HLA-DR4

Dao, Hien Thy, Loh, Tiing Jen, Sharma, Ravi K., Klareskog, Lars, Malmström, Vivianne, Reid, Hugh H., Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 and Lim, Jia Jia 2025. The molecular basis of T cell receptor recognition of citrullinated tenascin-C presented by HLA-DR4. Journal of Biological Chemistry , 110326. 10.1016/j.jbc.2025.110326

PDF - Accepted Post-Print Version Download (8MB)

Abstract

CD4+ T cell autoreactivity against citrullinated (cit) self-epitopes presented by HLA-DRB1 is associated with rheumatoid arthritis (RA) pathogenesis. We understand the molecular bases of T cell receptor (TCR) recognition of cit-fibrinogen, cit-vimentin, and cit-α-enolase epitopes, and the role of citrulline in shaping TCR repertoire usage. Nevertheless, how TCRs recognise other cit-epitopes, including tenascin-C (TNC) and how alternative citrullination positions may modulate the T cell recognition remains unclear. Here, we examined TNC1014,1016cit peptide, which contains citrullination at position P-1 and P2, to study the underlying TCR-HLA-DRB1*04:01- TNC1014,1016cit molecular interactions. Crystal structure of HLA-DRB1*04:01TNC1014,1016cit at 2.4 Å resolution revealed a conserved peptide binding register to the established HLA-DRB1*04:01-peptide structures, where both citrullines protruded upwards. Next, we determined the crystal structure of a RA patient-derived TRAV35+/TRBV10-2+ (PB) TCR in complex with HLA-DRB1*04:01TNC1014,1016cit at 3.2 Å resolution. The CDR3α loop (109VGNTN113) of PB TCR formed a secondary helical conformation at the N-terminus of the peptide binding cleft, allowing extensive interactions between the P-1 and P2 citrullines of TNC1014,1016cit peptide. Surface plasmon resonance, tetramer staining, and CD69 activation assays revealed that the PB TCR did not cross-react to other RA autoantigens, and the P-1-Cit, P2-Cit, and P5-Tyr of TNC1014,1016cit are the key determinants underlining the strict specificity of the PB TCR. Collectively, we provide molecular insight of citrullination in modulating TCR recognition.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Start Date: 2025-05-30
Publisher:	Elsevier
ISSN:	0021-9258
Date of First Compliant Deposit:	11 June 2025
Date of Acceptance:	28 May 2025
Last Modified:	11 Jun 2025 10:15
URI:	https://orca.cardiff.ac.uk/id/eprint/178998

Actions (repository staff only)

Edit Item