TCRβ clones in muscle tissue share structural features in patients with idiopathic inflammatory myopathy and are associated with disease activity

Front Immunol. 2024 Jan 10:14:1279055. doi: 10.3389/fimmu.2023.1279055. eCollection 2023.

Abstract

Objectives: To characterize the T cell receptor (TCRβ) repertoire in peripheral blood and muscle tissues of treatment naïve patients with newly diagnosed idiopathic inflammatory myopathies (IIMs).

Methods: High throughput RNA sequencing of the TCRβ chain was performed in peripheral blood and muscle tissue in twenty newly-diagnosed treatment-naïve IIM patients (9 DM, 5 NM/OM, 5 IMNM and 1 ASyS) and healthy controls. Results thereof were correlated with markers of disease activity.

Results: Muscle tissue of IIM patients shows more expansion of TCRβ clones and decreased diversity when compared to peripheral blood of IIM as well as healthy controls (both p=0.0001). Several expanded TCRβ clones in muscle are tissue restricted and cannot be retrieved in peripheral blood. These clones have significantly longer CDR3 regions when compared to clones (also) found in circulation (p=0.0002), while their CDR3 region is more hydrophobic (p<0.01). Network analysis shows that clonal TCRβ signatures are shared between patients. Increased clonal expansion in muscle tissue is significantly correlated with increased CK levels (p=0.03), while it tends to correlate with decreased muscle strength (p=0.08).

Conclusion: Network analysis of clones in muscle of IIM patients shows shared clusters of sequences across patients. Muscle-restricted CDR3 TCRβ clones show specific structural features in their T cell receptor. Our results indicate that clonal TCRβ expansion in muscle tissue might be associated with disease activity. Collectively, these findings support a role for specific clonal T cell responses in muscle tissue in the pathogenesis of the IIM subtypes studied.

Keywords: AIRR seq; T cell receptor (TCR); T cells; adaptive immunity; myositis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Clone Cells
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Muscles*
  • Myositis*
  • Receptors, Antigen, T-Cell / genetics

Substances

  • Receptors, Antigen, T-Cell

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. All patients were included in a study evaluating the effect of immunoglobulins as a first line treatment (19), which was funded by a grant (Interlaken Leadership Award) from CSL Behring. The funder had no role in the design of the original study, the analysis, collection, and interpretation of the data, and writing of the manuscript. The research leading to these results has received funding via a grant from ‘Stichting Remmert Adriaan Laan Fonds’. DCA and NdV were funded by the Horizon 2020 project COSMIC (www.cosmic-h2020.eu) under the Marie Skłodowska-Curie grant agreement No. 765158. This work was carried out on the Dutch national e-infrastructure with the support of SURF Foundation (e-infra180005).