Homocitrullinated Peptides Drive Pro-Inflammatory T-Cell Responses in a Humanized Mouse Model of Rheumatoid Arthritis.
basic_science · Level V
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- Record sourced from PubMed, PMID 42257519.
- Also identified by DOI 10.1002/art.70239.
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Abstract
Anti-homocitrullinated protein/peptide antibodies are specific to rheumatoid arthritis (RA) and predictive of worse prognosis, suggesting a pathogenic role for autoreactivity to homocitrullinated peptides (HomoCitP). However, T-cell responses to HomoCitP remain largely unexplored. We investigated these responses in a humanized HLA-DR4-transgenic (DR4tg) mouse model of RA, which expresses the strongest genetic risk factor for this disease. DR4tg mice (n=6-15) were injected subcutaneously with a HomoCitP called HomoCitJED while control mice received phosphate-buffered saline. After 10 days, T-cells were analyzed for their phenotypic characteristics, cytokine production, and proliferative capacities in draining lymph nodes (dLNs) and spleens by flow cytometry, enzyme-linked immunosorbent assays, and ProQuantum™ immunoassays. HomoCitJED immunization, compared with controls, drove robust expansion of T helper subsets in the dLNs, including more than a 7-fold increase in Th1, Th17, and hybrid Th1/Th17 cells (p<0.0087). Cytokine staining confirmed effector activity, with higher frequencies of IL-17A+, TNF-α+IL-17A+, and IFN-γ+IL-17A+ cells (p<0.0207). Exhaustion-associated markers were also increased, including LAG-3+ and Tim-3+ CD4+ T cells (p<0.0411). CD8+ T cells mirrored these findings, with a 6-fold increase in CD25 and doubled KLRG1 expression, accompanied by augmented IL-17A and IFN-γ/IL-17A production and antigen-specific proliferation (p<0.0379). Expression of exhaustion-associated markers Tim-3+ and LAG-3+ on CD8+ T cells was likewise elevated (p<0.0205). HomoCitP elicited Th1/Th17 and Tc1/Tc17 responses marked by concurrent expression of activation and exhaustion-associated markers, consistent with a dysregulated state. These findings position homocitrulline-driven CD4+ and CD8+ T-cell imbalance as a potential mechanistic contributor to RA pathogenesis and a target for future immunomodulatory therapies.