Endogenous antigens shape the transcriptome and TCR repertoire in an autoimmune arthritis model
Elizabeth E. McCarthy, … , Arthur Weiss, Judith F. Ashouri
Elizabeth E. McCarthy, … , Arthur Weiss, Judith F. Ashouri
Published November 26, 2024
Citation Information: J Clin Invest. 2025;135(2):e174647. https://doi.org/10.1172/JCI174647.
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Research Article Autoimmunity Immunology

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

Abstract

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 performed bulk and single-cell RNA-Seq (scRNA-Seq) and single-cell T cell receptor sequencing (scTCR-Seq) to profile a highly arthritogenic subset of naive CD4+ T cells from BALB/c-Zap70*W163C (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 exhibited heightened expression of T cell activation and cytokine signaling genes but diminished expression of a subset of tolerogenic markers (Izumo1r, Tnfrsf9, Cd5, S100a11) compared with WT cells. The arthritogenic cells showed an enrichment for TCR variable β (Vβ) chains targeting superantigens (Sags) from the endogenous mouse mammary tumor virus (MMTV) but exhibited diminished induction of tolerogenic markers following peripheral antigen encounter, contrasting with the robust induction of the negative regulators seen in WT cells. In arthritic joints, cells expressing Sag-reactive Vβs expanded alongside detectable MMTV proviruses. Antiretroviral treatment and Sag-reactive T cell depletion curtailed SKG arthritis, suggesting that endogenous retroviruses disrupted peripheral tolerance and promoted the activation and differentiation of autoreactive CD4+ T cells into pathogenic effector cells.

Authors

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

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Figure 6

Arthritogenic CD4+ T cells are enriched for TCR Vβs that are likely driven by endogenous Sags.

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Arthritogenic CD4+ T cells are enriched for TCR Vβs that are likely driv...
(A and B) Representative FACS plots (A) of peripheral naive or memory CD4+ T cells or joint CD4+ T cells, with the indicated TCR Vβ protein usage determined by flow cytometry in CD4+ T cells from dLNs or joints of SKGNur mice 2.5 weeks after arthritis induction with zymosan or mice treated with PBS vehicle (as seen in Supplemental Figure 8B) and quantification (B), where bar graphs depict the mean frequency (± SEM). (C) Bar graphs showing the GFP MFI (± SEM) of CD4+ T cells bearing the indicated Vβs from arthritic joints of SKG mice. n = 7 mice pooled from 2 experiments (also reported in Supplemental Figure 8D). (D and E) Representative FACS plots of (D) peripheral naive or memory CD4+ T cells or joint CD4+ T cells with the indicated TCR Vβ protein usage determined by flow cytometry in GFPlo (light blue) and GFPhi (dark blue) T cells from LNs or joints of SKGNur mice 2.5 weeks after arthritis induction with zymosan and quantification (E), in which bar graphs depict the mean frequency (± SEM). n = 7 mice per group pooled from 2 experiments. *P < 0.05, **P < 0.01, and ***P < 0.001, for FDR by 2-tailed paired t test with B-H correction; P value by exact permutation test (B and E); or FDR by linear mixed-effects model with B-H correction (C).