Identification of clonally expanded T-cell receptor sequences in giant cell arteritis

Background: Arterial wall inflammation in giant cell arteritis (GCA) is characterized by T-cell infiltration and granuloma formation. There have been limited studies investigating the diversity of the T-cell receptor (TCR) repertoire in GCA patients. Here we aim to identify disease-relevant TCRs. Methods: We sequenced the TCR beta repertoires in peripheral blood and biopsies from 72 GCA patients and compared them to repertoires of 60 age-matched controls. Applying K-nearest neighbours classification based on tcrdist3, an established TCR similarity measure, we identified GCA-associated TCRs across multiple model hyperparameters and experimental replicates. Results: We observed that species richness and Shannon diversity were significantly lower (P = 0.0003 and P = 0.004, respectively) in GCA peripheral blood TCR repertoires compared with age-matched controls. 1526 TCRs were identified that were consistently associated with GCA, 63 TCRs were also detected in TAB repertoires. Identical GCA-associated TCRs were observed in paired blood and tissue samples from 21/30 GCA cases. 57 % of GCA-associated TCRs were fitted into 10 clusters, which displayed distinct TCR sequences and TCR V and J segment usage. TRBV20-1*01, TRBV4-3*01, TRBV4-2*01 and TRBV4-1*01 segments were over-represented and occurred at least 10 % more often among GCA patients than age-matched controls. Only 27/1526 TCR sequences had matches reported in public databases, reducing the likelihood that these targeted common infectious agents. Conclusions: Our data provide evidence of circulating T-cell clonal expansions in GCA patients. Certain TCR sequence patterns were over-represented in GCA subjects. As more TCR sequences directed at human antigens become available, further analysis may ultimately reveal whether these TCRs bind a common target antigen.