Endogenous antigens shape the transcriptome and TCR repertoire in an autoimmune arthritis model

Elizabeth E. McCarthy; Steven Yu; Noah Perlmutter; Yuka Nakao; Ryota Naito; Charles Lin; Vivienne Riekher; Joe DeRisi; Chun Jimmie Ye; Arthur Weiss; Judith F. Ashouri

doi:10.1172/JCI174647

¹Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, United States of America

²Department of Medicine,Rosalind Russell and Ephraim P. Engleman Rheumatolog, University of California, San Francisco, San Francisco, United States of America

³Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States of America

⁴Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Fransisco, San Fransisco, United States of America

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¹Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, United States of America

²Department of Medicine,Rosalind Russell and Ephraim P. Engleman Rheumatolog, University of California, San Francisco, San Francisco, United States of America

³Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States of America

⁴Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Fransisco, San Fransisco, United States of America

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¹Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, United States of America

²Department of Medicine,Rosalind Russell and Ephraim P. Engleman Rheumatolog, University of California, San Francisco, San Francisco, United States of America

³Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States of America

⁴Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Fransisco, San Fransisco, United States of America

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¹Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, United States of America

²Department of Medicine,Rosalind Russell and Ephraim P. Engleman Rheumatolog, University of California, San Francisco, San Francisco, United States of America

³Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States of America

⁴Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Fransisco, San Fransisco, United States of America

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¹Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, United States of America

²Department of Medicine,Rosalind Russell and Ephraim P. Engleman Rheumatolog, University of California, San Francisco, San Francisco, United States of America

³Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States of America

⁴Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Fransisco, San Fransisco, United States of America

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¹Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, United States of America

²Department of Medicine,Rosalind Russell and Ephraim P. Engleman Rheumatolog, University of California, San Francisco, San Francisco, United States of America

³Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States of America

⁴Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Fransisco, San Fransisco, United States of America

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¹Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, United States of America

²Department of Medicine,Rosalind Russell and Ephraim P. Engleman Rheumatolog, University of California, San Francisco, San Francisco, United States of America

³Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States of America

⁴Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Fransisco, San Fransisco, United States of America

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¹Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, United States of America

²Department of Medicine,Rosalind Russell and Ephraim P. Engleman Rheumatolog, University of California, San Francisco, San Francisco, United States of America

³Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States of America

⁴Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Fransisco, San Fransisco, United States of America

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¹Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, United States of America

²Department of Medicine,Rosalind Russell and Ephraim P. Engleman Rheumatolog, University of California, San Francisco, San Francisco, United States of America

³Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States of America

⁴Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Fransisco, San Fransisco, United States of America

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¹Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, United States of America

²Department of Medicine,Rosalind Russell and Ephraim P. Engleman Rheumatolog, University of California, San Francisco, San Francisco, United States of America

³Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States of America

⁴Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Fransisco, San Fransisco, United States of America

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¹Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Francisco, San Francisco, United States of America

²Department of Medicine,Rosalind Russell and Ephraim P. Engleman Rheumatolog, University of California, San Francisco, San Francisco, United States of America

³Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States of America

⁴Rosalind Russell and Ephraim P. Engleman Rheumatology Research Center, University of California, San Fransisco, San Fransisco, United States of America

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J Clin Invest. https://doi.org/10.1172/JCI174647.
Copyright © 2024, McCarthy et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published November 26, 2024 - Version history

The development of pathogenic autoreactive CD4⁺ T cells, particularly in the context of impaired signaling, remains poorly understood. Unraveling how defective signaling pathways contribute to their activation and persistence is crucial for identifying new therapeutic targets. We profiled a highly arthritogenic subset of naïve CD4⁺ T cells using bulk and single-cell RNA and TCR sequencing from SKG mice, which develop CD4⁺ T cell mediated autoimmune arthritis driven by a hypomorphic mutation in Zap70—a key TCR signaling kinase. Despite impaired signaling, these cells exhibit heightened expression of T cell activation and cytokine signaling genes, but diminished expression of a subset of tolerogenic markers (Izumo1r, Tnfrsf9, Cd5, S100a11) compared to wild-type cells. The arthritogenic cells show an enrichment for TCR variable beta (Vβ) chains targeting superantigens from the endogenous mouse mammary tumor virus (MMTV) but exhibit diminished induction of tolerogenic markers following peripheral antigen encounter, contrasting with the robust induction of negative regulators seen in wild-type cells. In arthritic joints, cells expressing superantigen-reactive Vβs expand alongside detectable MMTV proviruses. Antiretroviral treatment and superantigen-reactive T cell depletion curtail SKG arthritis, suggesting that endogenous retroviruses disrupt peripheral tolerance and promote the activation and differentiation of self-reactive CD4⁺ T cells into pathogenic effector cells.

Version 1 (November 26, 2024): In-Press Preview

Endogenous antigens shape the transcriptome and TCR repertoire in an autoimmune arthritis model

Elizabeth E. McCarthy,¹ Steven Yu,¹ Noah Perlmutter,¹ Yuka Nakao,¹ Ryota Naito,¹ Charles Lin,² Vivienne Riekher,² Joe DeRisi,³ Chun Jimmie Ye,¹ Arthur Weiss,⁴ and Judith F. Ashouri¹

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Endogenous antigens shape the transcriptome and TCR repertoire in an autoimmune arthritis model

Elizabeth E. McCarthy,1 Steven Yu,1 Noah Perlmutter,1 Yuka Nakao,1 Ryota Naito,1 Charles Lin,2 Vivienne Riekher,2 Joe DeRisi,3 Chun Jimmie Ye,1 Arthur Weiss,4 and Judith F. Ashouri1

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Elizabeth E. McCarthy,¹ Steven Yu,¹ Noah Perlmutter,¹ Yuka Nakao,¹ Ryota Naito,¹ Charles Lin,² Vivienne Riekher,² Joe DeRisi,³ Chun Jimmie Ye,¹ Arthur Weiss,⁴ and Judith F. Ashouri¹